Can omalizumab synergize immunotherapy
Thomas B. Casale, M.D.
Professor and Associate Chair of Medicine
Chief, Allergy and Immunology
- Understand the mechanisms of action of omalizumab and immunotherapy.
- Discuss the rationale for combining omalizumab and immunotherapy for the treatment of allergic diseases.
- Summarize the efficacy and safety of omalizumab pretreatment for patients undergoing allergen-specific immunotherapy
Current therapies for allergic rhinitis and asthma include allergen avoidance; pharmacologic interventions such as topical and systemic corticosteroids, and immunotherapy. Although pharmacologic agents are often effective for many patients, their role is sometimes limited by their inability to completely relieve symptoms, and in some cases, the induction of deleterious side effects. Immunotherapy regimens can be highly effective in controlling symptoms of allergic rhinitis and asthma and can offer advantages over pharmacotherapy for those patients who have symptoms that are refractory to medications or those who cannot tolerate the side effects. However, immunotherapy is associated with the risk of allergic reactions to the extract injections. Furthermore, the effectiveness of allergen-immunotherapy for allergic respiratory diseases is not always evident, especially in asthma.
Omalizumab, a monoclonal antibody against IgE has been approved in many countries for the treatment of moderate to severe persistent allergic asthma. Omalizumab has been shown to be safe and effective for the treatment of children and adults with seasonal and perennial allergic rhinitis as well as allergic asthma. It causes a dose-related decrease in serum IgE levels that is associated with improvement in symptoms. Omalizumab has been shown to both prevent the development of symptoms, and treat established allergic disorders Omalizumab does not completely ameliorate symptoms of allergic respiratory symptoms, and upon discontinuation, serum IgE levels return to pre-treatment levels. Furthermore, there are no data concerning long lasting immune tolerance as a result of anti-IgE therapy.
Thus, there is a need for safer and more effective therapies capable of inducing an immune tolerant state. The combination of anti-IgE and allergen immunotherapy holds promise for such therapy.
The rationale for using the combination of anti-IgE and allergen immunotherapy comes from pre-existing data about the biologic and immunologic effects of both therapies. Allergen immunotherapy has been used for more than ninety years for the management of allergic disorders, including seasonal and perennial allergic rhinitis, allergic asthma and hymenoptera sensitivity. Immunotherapy is the only antigen-specific immunomodulatory treatment routinely available to clinicians. It can provide long-term benefits and modify the natural history of allergic diseases, preventing the development of neo-sensitization and asthma in children. The immunomodulatory effects of immunotherapy are due to a number of mechanisms. Immunotherapy blunts seasonal increases in IgE levels and leads to increases in allergen-specific IgG levels, especially IgG 4. This results in decreased IgE-mediated histamine release and inhibition of IgE-mediated antigen presentation to T-cells. Furthermore, the binding capacity of IgG 4 is increased, whereas that for IgE is decreased after long term immunotherapy. In addition, immunotherapy has profound effects on lymphocytes. Although somewhat controversial, immunotherapy appears to shift the balance of T-lymphocyte subsets away from a Th2 phenotype and toward a Th1 phenotype. Furthermore, immunotherapy leads to the production of allergen-specific IL-10. IL-10 has a number of biological consequences that could be important in mediating the immunotolerogenic effects of immunotherapy. These effects include modulation of IL-4-induced B-cell IgE production in favor of IgG 4, inhibition of IgE-dependent mast cell activation, inhibition of human eosinophils including decreased cytokine production and survival, suppression of IL-5, and induction of allergen-specific anergy. Finally, the importance of not only IL-10, but regulatory T-cells and dendritic cells in mediating the therapeutic effects of immunotherapy is just being elucidated.
Omalizumab decreases serum IgE and the expression of FcεR1 on key immune effector cells including dendritic cells, monocytes, mast cells and basophils. Each of these effects could lead to important immunologic changes that could enhance the immune tolerance to allergens delivered by immunotherapy. However, unlike immunotherapy, omalizumab has not been shown to provide long-lasting immunotolerogenic and therapeutic effects after discontinuing treatment.
The rationale for combining omalizumab plus allergen immunotherapy includes the prospects of improved clinical benefits and immunotolerogenic effects. Furthermore, by decreasing serum IgE levels and FceR1 expression, omalizumab should make immunotherapy safer.
In a study conducted by the Omalizumab Rhinitis Study Group, the effects of adding omalizumab to immunotherapy were examined in children. Subjects underwent a pre-screening phase and then over a twelve-week period received immunotherapy up to a maintenance dosage. Subjects were then randomized to receive either omalizumab or placebo as an add-on therapy for twenty-four additional weeks. Inclusion criteria included 6 to 17 years of age, two year history of moderate-to-severe seasonal allergic rhinitis due to birch and grass pollen, FEV1 values greater than 70% and serum IgE levels between 30 and 1300 IU/ml. 221 subjects were enrolled. The combination of immunotherapy plus omalizumab was more effective than either therapy alone or placebo. For example, the combination of immunotherapy plus omalizumab versus immunotherapy alone produced a reduction in seasonal allergic rhinitis symptoms of 35% for the birch and 45% for grass immunotherapy groups, respectively; rescue medication scores of 78% for birch and 81% for grass immunotherapy; and seasonal allergic rhinitis symptom load of 40% for both grass and birch groups; and a safety profile at least as good as immunotherapy alone.
More recently, the results of a NIH/ImmuneTolerance Network sponsored study examining the effects of pre-treatment of ragweed allergic rhinitis patients with omalizumab prior to immunotherapy was published. The hypothesis was that pre-treatment of ragweed allergic patients with omalizumab will condition the recipient so that subsequent administration of ragweed allergen immunotherapy is safer, clinically more effective and immunologically more efficient at inducing a long-lasting immune tolerance to ragweed. The specific aims were to:
- Examine whether omalizumab given nine weeks prior to rush immunotherapy (RIT) followed by twelve weeks of dual omalizumab plus immunotherapy is safer and more effective than immunotherapy alone (primary objective) and omalizumab alone and placebo (secondary objectives) in preventing symptoms of ragweed-induced seasonal allergic rhinitis;
- Study the immunologic mechanisms of action associated with these therapies;
- Study whether there is an induction of tolerance after discontinuing these therapies as manifested by persistent inhibition of in vivo challenges and prolonged in vitro immunologic changes indicative of tolerance.
Omalizumab preceding immunotherapy should theoretically provide greater safety for immunotherapy by not only reducing serum IgE and high affinity IgE receptor expression, but perhaps by leading to a different mode of antigen presentation. In addition, omalizumab should allow more rapid antigen administration and the use of greater amounts of antigen in immunotherapy.
This was a phase II, double-blind, parallel group, three center, placebo-controlled study. Patients were screened between April 7 and approximately May 13, 2003. Omalizumab (0.016mg/kg/IgE [IU/ml]) or omalizumab placebo pre-treatment was then begun for nine weeks. This was followed by a five hour rush or placebo immunotherapy day. Subsequently, patients received omalizumab or placebo and immunotherapy or placebo immunotherapy for twelve weeks up to September 29, 2003.
Patients were followed over a second ragweed season off immunotherapy and omalizumab to determine whether there are long-lasting effects of the therapy.
The primary endpoint was the average daily allergy severity score which included sneezing, nasal congestion/stuffiness, itchy nose, throat and palate; itchy, watery eyes; and rhinorrhea. Secondary endpoints included incidence and severity of adverse events, the number of days with rescue medication use, the number of rescue medication capsules used, RQLQ scores, daily AM/PM symptom scores, minimal symptom days, individual allergy symptom scores, and in vivo/in vitro immunologic assays. Major inclusion/exclusion criteria included a history of ragweed seasonal allergic rhinitis symptoms for greater than or equal to two years requiring pharmacotherapy, a positive skin prick test to ragweed, IgE levels between 10 and 700, no asthma, and no prior treatment with monoclonal antibodies or immunotherapy.
The groups were evenly divided in regards to age and gender. The mean age was approximately 33 years and there was a slight predominance of females. Serum IgE levels range from 10 to 650 with a mean of 91 to 118 in the four groups. 159 total subjects were randomized. Of these 159 patients, 123 completed all treatments. Ragweed-specific IgG levels increased >11-fold in immunotherapy patients, and free IgE levels declined >10-fold in omalizumab patients.
The number, scope and severity of adverse events associated with RIT were highest in those patients receiving immunotherapy only. Only small differences in the percentage of patients with adverse events were noted between treatment arms receiving omalizumab plus immunotherapy, omalizumab alone and placebo/placebo. In contrast, the patients receiving immunotherapy only had a much greater rate of allergic-like reactions during RIT, and the percentage of these patients having allergic-like reactions during the RIT was allergen dose-dependent, as shown in Figure 2. More patients in the immunotherapy only group (20.5%) versus the group receiving omalizumab plus immunotherapy (13.9%) received epinephrine for allergic-like reactions on the RIT day. The percentages of patients with serious adverse events during RIT were 2.6, 0, 15.0, and 5.0 for the omalizumab plus immunotherapy, omalizumab only, immunotherapy only and placebo only groups, respectively. Allergic-like reaction rates in the omalizumab alone and placebo groups were 0 and 2.7%, respectively.
Overall rates of allergic reactions during RIT (including those treated before or after July 1, 2003) were 33.3% omalizumab plus IT; 29.7% omalizumab plus placebo; 56.4% placebo plus immunotherapy; and 18.9% placebo/placebo. Pairwise comparisons of adverse events in each group illustrate that immunotherapy alone was associated with a greater than five-fold, significant increase in risk of adverse events compared to placebo (OR=5.41; p=0.001). This significant increase is lost with the addition of omalizumab to RIT, which carried only an approximately two-fold risk of adverse events compared to placebo (OR=2.12; p=0.19). After RIT, comparison of groups receiving build-up or maintenance immunotherapy with or without omalizumab revealed a trend towards a decreased risk of adverse events with the addition of omalizumab (OR=0.39), although statistical significance was not reached (p=0.064), possibly due to the low frequency of events. No significant differences in the incidence of immediate post-injection adverse events were observed between groups during the build-up and maintenance phase.
Results of a post-hoc blinded analysis of patients judged to have anaphylactic reactions (defined as reactions involving two or more organ systems concurrently and/or severe enough to require epinephrine; judged by independent observers) during RIT also indicated a protective effect of omalizumab (Table II). In pair-wise analysis, immunotherapy alone was shown to significantly increase the risk of anaphylaxis compared to placebo (OR=12.08; p=0.007), whereas the addition of omalizumab reduced this increased risk to levels that were no longer significant (OR=2.10; p=0.615). A comparison of groups receiving immunotherapy (omalizumab + IT vs IT-only) demonstrated that the addition of omalizumab resulted in a significant, five-fold decrease in risk of anaphylaxis due to RIT (OR=0.17; p=0.026). Using the same definition [of anaphylaxis], 0% of patients in the omalizumab plus immunotherapy arm versus 9.7% in the placebo plus immunotherapy arm had anaphylaxis during the weekly build-up/maintenance phase of immunotherapy, but this difference did not reach statistical significance (p=0.238), perhaps reflecting the low number of anaphylactic events during IT.
The average daily allergy severity scores were significantly better in the omalizumab plus immunotherapy group versus the immunotherapy alone group. Furthermore, in protocol correct patients, the combination of omalizumab plus immunotherapy was better than omalizumab alone, immunotherapy alone or placebo alone (Figure 3).
The data suggest that omalizumab pre-treatment may be an effective strategy to permit more rapid and high doses of allergen immunotherapy to be used. If the exact dosing and timing of the omalizumab pretreatment can be determined, pretreatment with the anti-IgE monoclonal antibody might ultimately prove to be a major step forward in the use of allergen-specific immunotherapy for a wider variety of patients and disorders.. The mechanisms involved in improved efficacy and safety of omalizumab and immunotherapy are still under investigation.
There are still some important questions regarding this approach including:
How Long Should Omalizumab Pretreatment Be For Asthma Trials?
- Data to date:
- Nasal challenges: 2 wks
- FCeRI expression: 2 wks
- Skin challenges: 8-10 wks
- Asthma improvement: 12-16 wks
- Rush immunotherapy: 9 wks
- Data suggest that to achieve a safer IT regimen --- should treat for >12 weeks.
Unanswered Questions Include:
- How long do you need to treat with both?
- Can you stop the omalizumab after reaching maintenance IT?
- What are the immunologic and clinical endpoints of interest, and when do you measure them?
- Will this approach work for moderate/severe asthma?
References (listed chronologically)
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