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Table 2. Recommended dosing with US standardized extracts.
Allergen Extracts Available in
the US
Short ragweed 1/10 w/v
(100,000 AU/mL)
Timothy grass 100,000 BAU/mL 2,500 BAU
Bermuda grass 10,000 BAU/mL 900 BAU
Cat hair and dander 5,000, 10,000 BAU/mL 2,500 BAU
Dermatophagoides
pteronyssinus
Dermatophagoides
farinae
1
Modified from Cox 2011.
3,000, 5,000, 10,000
and 30,000 AU/mL
3,000, 5,000, 10,000,
and 30,000 AU/mL
Dosing Recommended in Practice
Parameter Mean (Range)
2,500 AU
(1,000 to 4,000 AU)
(1,000 to 4,000 BAU)
(300 to 1,500 BAU)
(1,000 to 4,000 BAU)
1,250 AU
(500 to 2,000 AU)
1,250 AU
(500 to 2,000 AU)
1
extracts; accordingly, it is not known if effective AIT can be delivered with the presently available
US commercial extracts. It is not customary to adjust the targeted dose for age or weight.
Attention to Cross-Allergenicity
It is important that cross-reacting allergen extracts be approached differently from non-cross-reacting
extracts. To prevent overloading the treatment extract with a group of cross-reacting allergens, either
the locally predominating species should be used to represent the group or a mixture of locally
important members of the group should be prepared and treated as if they were a single pollen
extract. Clinically important cross-reacting groups are listed in Table 3.
Table 3. Patterns of cross-reactivity of allergens.
Trees
Birch; Alder; Hazelnut; Hornbeam (strongly cross-reactive);
Beech; Oak (moderately cross-reactive)
European Olive; Ash; Privet; Russian Olive Use locally most important species
Cedar; Cypress; Juniper; Arborvitae Use locally most important species
Pecan; Hickory Use locally most important species
Poplar; Aspen; Cottonwood Use locally most important species
Grasses
NPG (Timothy; June; Orchard; Redtop; Meadow Fescue; Perennial
Rye; Sweet Vernal
Bermuda Grass Not cross-reactive with NPG
Bahia, Johnson Grass Use if locally important
Weeds
Short; Giant; False and Western Ragweed Use locally most important species
Southern and Slender Ragweed; Cocklebur, Burweed Marsh Elder Use if locally important
Sages; Mugwort Use locally most important species
Pigweed; Palmer’s Amaranth; Western Water Hemp Use locally most important species
Russian Thistle; Kochia; Lamb’s Quarters If both Russian Thistle and Kochia are locally
Insects
Dermatophagoides pteronyssinus and farinae
Cockroach; German and American Use a mixture
1
From: Weber 2007 and Weber 2008.
Use locally most important species
Use Timothy or a mixture of locally important
members
important, use a mixture
If both are locally important, use a mixture
1
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Compatibility of Allergy Extracts for Mixing
Allergen extracts of cockroaches and fungi have strong proteolytic activities that have been shown
to degrade the allergens contained in each other (Grier 2012) as well as extracts of pollens, animal
danders and house dust mites (Nelson 1996). The proper procedure is that cockroach and fungal
extracts are given separately and neither is mixed with pollen, dander or house dust mite extracts.
Preparing an Allergen Extract for AIT
A physician with training and expertise in allergen immunotherapy should be responsible for
ensuring that compounding personnel are instructed and trained in the preparation of extracts for
AIT (Cox 2011).
Single extracts or mixtures of allergen extracts suitable for AIT can be obtained from most
commercial providers of allergen extracts. These will contain the proper concentration of the
extract(s) that have been prepared under sterile conditions and will contain multiple vials of
increasing concentration of the treatment extract to be used to build up to the maintenance dose
unless this represents a refill of the maintenance concentration.
If, on the other hand, the extract for AIT is to be prepared in the clinic of the prescribing
physician, there are conditions that should be met (Cox 2011). The compounding person must:
1. Be an appropriately trained health professional
2. Be trained in the preparation of allergenic products
3. Pass a written test on aseptic technique and extract preparation
4. Be able to correctly identify, measure and mix ingredients
5. Be able to demonstrate an understanding of antiseptic hand cleaning and disinfection of
mixing surfaces
6. Annually pass a media-fill test
Competency can be assessed using quizzes prepared by the Advocacy Council of the American
College of Allergy, Asthma and Immunology at (https://education.acaai.org, then under “Free
courses for College members”, highlight “allergen extract mixing quiz” (accessed June 7, 2023).
Non-college members should go to (https://education.acaai.org/allergenextractquiznm) (ACAAI
2023b). The following additional resources are available with the quizzes: The ACAAI’s Allergen
Immunotherapy Extract Preparation: Physician Instruction Guide; An Allergen Extract Preparationcompetency Check List to use in preparation for taking the Extract Preparation Quiz; the Allergen
Extract Preparation Guidelines; and the portion of U.S. Pharmacopoeia Convention (USP) Chapter
797 that relates to allergen extract preparation.
Several commercial tests are available to assess sterile technique (i.e., media-fill tests).
Information is available through the American College of Allergy, Asthma and Immunology at
(hppts://education.acaai.org) (ACAAI 2023b) accessed June 7, 2023.
Management of AIT
Build-up Schedule
SCIT treatment must be started with a diluted extract, usually 1:1,000 v/v of the maintenance
concentration in patients with no special risk (Table 4).
A somewhat more conservative build-up is recommended for patients with many strongly
positive skin prick tests, controlled asthma or a history of systemic reactions to previous AIT. The
build-up may be accomplished with injection visits once or twice a week or even daily, by cluster
build-up with several injections per day on non-consecutive days by rush build-up with multiple
injections on consecutive days (https://college.acaai.org/toolkits/allergen-extract-mixing-toolkit/)
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Table 4. Representative conventional schedule for subcutaneous immunotherapy.1 Patients with asthma or previous systemic
reactions to AIT may require a more conservative schedule.
1:10,000 v/v
From (Nelson 2021)
Vial #5 is used for highly sensitive patients (multiple large skin test reactions). Less sensitive patients begin with vial #4.
Vial #5
Silver Cap
0.05 mL
0.10 mL
0.20 mL
0.40 mL
2
1:1,000 v/v
Vial #4
Blue Cap
0.05 mL
0.10 mL
0.20 mL
0.40 mL
1:100 v/v
Vial #3
Green Cap
0.05 mL
0.10 mL
0.20 mL
0.40 mL
1:10 v/v
Vial #2
Gold Cap
0.05 mL
0.07 mL
0.10 mL
0.15 mL
0.25 mL
0.35 mL
0.50 mL
1:1 v/v
Maintenance
Vial
Red Cap
0.05 mL
0.07 mL
0.10 mL
0.15 mL
0.20 mL
0.30 mL
0.40 mL
0.50 mL
(ACAAI 2023a). The advantage of cluster and rush regimens is more rapidly reaching maintenance
doses. The disadvantage of rush is more frequent systemic reactions. There is disagreement about
whether cluster build up is associated with an increased incidence of systemic reactions (Epstein
2013; Winslow 2016). Whatever schedule is used, it is important to keep the extract at 4 degrees
centigrade when the patient is not actually receiving their injection to avoid accelerated loss of
potency. Loss of potency is more rapid in more dilute solutions, making it important to complete
treatment with the first 1–2 vials as quickly as possible.
Although build-up schedules have been employed with SLIT, treatment with the currently
approved SLIT tablets is initiated with the maintenance dose tablet.
Safety Precautions
No matter which build-up schedule is used, certain precautions are employed by some or all
physicians in administering AIT. For SCIT, the treatment should be administered in a medical
facility with trained personnel and equipment to manage systemic reactions (Cox 2011), use of two
means of identification (such as name and birth date) should be used to ensure the administration of
the correct extract to the patient, and the patient should remain under observation in the facility for
30 minutes following the injection (Cox 2011). If the patient has asthma, special care is indicated
including determining that the asthma is well controlled because, if not, the injection should not be
given (Cox 2011). The occurrence of large local or systemic reactions with SCIT can be reduced by
the pre-administration of an antihistamine (Ohashi 2006).
Two safety concerns are quite controversial, prescribing an epinephrine autoinjector for all or
most patients receiving SCIT (Epstein 2019) (the FDA mandates this for patients receiving SLIT
tablets since administration occurs at home) and reduction in the dose of SCIT during the season of
pollen contained in their treatment extract (Bernstein 2020; Lin 1992; Wong 2017). US allergists are
close to evenly divided on both issues.
With SLIT, where the occurrence of serious systemic reactions is very uncommon except with
the initial dose, the first dose should be administered under observation in the clinic, but subsequent
doses are administered by the patient at home.
Modification in Doses
The dose of the SCIT extract may require reduction under certain circumstances such as
1. replacement of the maintenance extract when the previous vial is exhausted or expired;
2. an excessive number of consecutively missed injection visits; or the occurrence of a systemic
reaction.
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Table 5. Adjustments for gaps in SCIT treatment.
Build-up Phase
Up to 7 days late Continue build-up as scheduled
8–13 days Repeat the last dose
14–21 days Reduce dose by 25%
21–28 days Reduce dose by 50%
Maintenance Phase
2–4 weeks late Reduce dose by 75%
> weeks late Reduce by one or more dilutions depending on the length of time and the patient’s sensitivity
1
Modified from the US Practice Parameters (Cox 2011).
1
While it is clear that all these situations require some adjustment in dose, there are few
prospective studies testing the safety of different degrees of modifications. Empiric suggestions
for adjustment for new vials is that the dose is reduced by 1/3 to 1/2 if the same extracts from
the same providers are used to compound the new extract. This drop-back should be greater (e.g.,
90%) if there is a change in the supplier of allergen extracts and still greater (e.g., 99%) if fungal
or cockroach extracts are included. Suggestions for adjusting for missed doses are given in Table 5.
If the patient experiences a systemic reaction during build up, common practice is to administer
the last tolerated dose the next time. If the reaction is severe or the patient is on maintenance, some
reduction in dose is common. Also, if the reaction is severe, the physician should assess, with input
from the patient, the appropriateness of continuing AIT.
Large Local Reactions
Large local reactions are common during the course of SCIT. They have been shown not to be
predictive of a systemic reaction with the next injection (Tankersley 2000; Jutel and Kelso 2004)
but may persist for 24 hours or more and cause patients discomfort. Two studies have demonstrated
that the occurrence of large local reactions can be reduced by rinsing the syringe with epinephrine
1:1,000 prior to filling it with extract (Mustafa 2020; Sapsaprang 2020).
Duration of AIT
Studies of 3 or 4 years of SCIT with grass pollen extract have shown good clinical responses
and persistence of improvement during 3 years of follow-up after AIT was stopped (Ebner 1994;
Durham 1999). Other SCIT studies have shown that in patients with residual symptoms after 3 years
2 further years of treatment produced significant further improvement (Tabar 2011) or produced no
further improvement (Stelmach et al. 2012). Thus, the usual recommendation is 3–5 years of AIT
depending on how quickly the patient responds but stopping AIT if the patient has not responded by
one year after reaching maintenance dosing.
A study with house dust mite SLIT found a good response with 3-year treatment, but a somewhat
more prolonged remission with 4 or 5 years of treatment (Marogna et al. 2010). On the other hand, a
study of both SCIT and SLIT treatment for 2 years found that the improvement with both approaches
versus placebo, was significant after 2 years, but the benefit was largely lost one year after treatment
was discontinued (Scadding et al. 2017) suggesting 2 years of either SCIT or SLIT, even if clinically
effective while being administered was, of insufficient duration to provide long-lasting relief.
Future Approaches to AIT
Despite the overall efficacy and disease-modifying potential of SCIT and SLIT, both are underutilized
in treating the increasing number of patients with respiratory allergies. Both involve some expense
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for most patients. SCIT, although probably somewhat more effective than SLIT, is associated with
an increased potential for systemic reactions; for that reason, it must be administered in a facility
prepared to treat these reactions. SCIT, on the other hand, can be self-administered at home. A big
drawback is that both SCIT and SLIT involve a 3- to 5-year commitment and a number of studies
suggest that a relatively small percentage placed on AIT persist with the treatment for that length
of time that is probably necessary to achieve persisting improvement. The mechanisms underlying
the improvement with AIT are thought to be understood, which encourages investigators to pursue
new ways to achieve these immunologic changes by methods that require many fewer treatments,
hopefully over a shorter period. Table 1 lists the more promising approaches that are currently under
investigation to achieve improvements in SCIT (Nelson 2022). Of these, the most likely to see
introduction into clinical use is the alternative routes of administration, the adjuvants vitamin D and
probiotics and the allergoids. The other approaches will require extensive investigations and even if
they succeed, they are a number of years away from approval.
Glossary of Abbreviations
ACAAI – American College of Allergy, Asthma and Immunology
AIT – Allergy Immunotherapy
AU – Allergy Units
AQ – Aqueous
AP – Aluminum Precipitated
BAU – Bioequivalent Allergy Units
EAACI – European Academy of Allergy and Clinical Immunology
GPS – Grass Pollen Season
HAS – Human Serum Albumin
50% G – 50% Glycerin
NPG – Northern Pasture Grasses
OIT – Oral Immunotherapy
PNU – Protein Nitrogen Units
RDBPC – Randomized, Double-Blind, Placebo-Controlled Trials
SCIT – Subcutaneous Immunotherapy
SLIT – Sublingual Immunotherapy
w/v – Weight by Volume
Aasbjerg, K., Backer, V., Lund, G., Holm, J., Nielsen, N. C., Holse, M. et al. 2014. Immunological comparison of
allergen immunotherapy tablet treatment and subcutaneous immunotherapy against grass allergy. Clin. Exp.
Allergy 44: 417–28.
ACAAI. 2023a. (https://college.acaai.org/toolkits/allergen-extract-mixing-toolkit/).
ACAAI. 2023b. (hppts://education.acaai.org).
Bae, J. M., Choi, Y. Y., Park, C. O., Chung, K. Y. and Lee, K. H. 2013. Efficacy of allergen-specific immunotherapy
for atopic dermatitis: a systematic review and meta-analysis of randomized controlled trials. J. Allergy Clin.
Immunol. 132: 110–7.
Bernstein, D. and Epstein, T. E. G. 2020. Safety of allergen immunotherapy in North America from 2008–2017:
Lessons learned from the ACAAI/AAAAI National Surveillance Study of adverse reactions to allergen
immunotherapy. Allergy Asthma Proc. 41: 108–111.
Boyle, R. J., Eiremeli, M., Hockenhull, J, Cherry, M. G., Bulsara, M. K., Daniels, M. and Oude Eiberink, J. N. G.
2012. Venom immunotherapy for preventing allergic reactions to insect stings. Cochrane Database Syst. Rev.
10: CD008838.
Burks, A. W., Calderon, M. A., Casale, T., Cox, L., Demoly, P., Jutel, M. et al. 2013. Update on allergy immunotherapy:
American Academy of Allergy, Asthma & Immunology/European Academy of Allergy and Clinical Immunology/
PRACTALL consensus report. J. Allergy Clin. Immunol. 131: 1288–96.
References
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Calderon, M. A., Casale, T. B., Togias, A., Bousquet, J., Durham, S. R. and Demoly, P. 2011. Allergen-specific
immunotherapy for respiratory allergies: from meta-analysis to registration and beyond. J. Allergy Clin.
Immunol. 127: 30–38.
Cox, L., Nelson, H., Lockey, R, Calabria, C., Chacko, T., Finegold, I. et al. 2011. Allergen immunotherapy: a practice
parameter third update. J. Allergy Clin. Immunol. 127: S1–S55.
Demoly, P., Passalacqua, G., Pfaar, O., Sastre, J. and Wahn, U. 2016. Management of the polyallergic patients with
allergy immunotherapy: a practice-based approach. Allergy Asthma Clin. Immunol. 12: 2.
Durham, S. R., Walker, S. M., Varga, E. M., Jacobson, M. R., O’Brien, F. O., Noble, W. et al. 1999. Long-term clinical
efficacy of grass-pollen immunotherapy. N Engl. J. Med. 341: 468–75.
Ebner, C., Kraft, D. and Ebner, H. 1994. Booster immunotherapy (BIT). Allergy 49: 38–42.
Epsein, T. G., Liss, G. M., Murphy-Berendts, K. and Bernstein, D. I. 2013. AAAAI and ACAAI surveillance study
of subcutaneous immunotherapy, Year 3: what practices modify the risk of systemic reactions? Ann. Allergy
Asthma Immunol. 110: 274–8.
Epstein, T. G., Liss, G. M., Berendts, K. M. and Bernstein, D. I. 2019. AAAAI/ACAAI Subcutaneous Immunotherapy
Surveillance Study 2013–2017: fatalities, infections delayed reactions, and use of epinephrine autoinjectors.
J. Allergy Clin. Immunol. Pract. 7: 1996–2003.
Epstein, T. G., Murphy-Berendts, K., Liss, G. M. and Bernstein, D. 2021. Risk factors for fatal and nonfatal reactions
to immunotherapy (2008–2018): postinjection monitoring and severe asthma. Ann. Allergy Asthma Immunol.
127: 64–69.
Franklin, W. and Lowell, F. C. 1967. Comparison of two dosages of ragweed extract in the treatment of pollinosis.
JAMA 201: 915–917.
Fulmali, A. and Kimkool, P. 2021. Is sublingual immunotherapy for asthma effective and safe? J. Allergy Clin.
Immunol. 147: 1865–1872.
Grier, T. J., LeFevre, D. M., Duncan, E. A., Esch, R. E. and Coyne, T. C. 2012. Allergen stabilities and compatibilities
in mixtures of high-protease fungal and insect extracts. Ann. Allergy Asthma Immunol. 108: 439–47.
Hamid, Q. A., Schotman, E., Jacobson, M. R., Walker, S. M. and Durham, S. R. 1997. Increases in IL-12 messenger
RNA+ cells accompany inhibition of allergen-induced late skin responses after successful grass pollen
immunotherapy. J. Allergy Clin. Immunol. 99: 254–60.
Jutel, M. and Kelso, J. M. 2004. The rate of systemic reactions to immunotherapy injections is the same whether or
not the dose is reduced after a local reaction. Ann. Allergy Asthma Immunol. 92: 225–227.
Kiel, M. A., Röder, E., Gerth van Wijk, R., Al, M. J., Hop, W. C. and Rutten van Mölken, M. P. 2013. Real-life
compliance and persistence among users of subcutaneous and sublingual allergen immunotherapy. J. Allergy
Clin. Immunol. 132: 353–360.
Lin, M. S., Tanner, E., Lynn, J. and Friday, G. A. Jr. 1992. Nonfatal systemic allergic reactions induced by skin testing
and immunotherapy. Ann. Allergy 71: 557–562.
Lowell, F. C. and Franklin, W. 1965. A double-blind study of the effectiveness and specificity of injection therapy in
ragweed hay fever. N Engl. J. Med. 273: 675–679.
Marogna, M., Spadolini, I., Massolo, A., Canonica, G. W. and Passalacqua, G. 2010. Long-lasting effects of sublingual
immunotherapy according to its duration: a 15-year prospective study. J. Allergy Clin. Immunol. 126: 969–75.
Meiser, J. B. and Nelson, H. S. 2001. Comparing conventional and acetone-precipitated dog allergen extract skin
testing. J. Allergy Clin. Immunol. 107: 744–745.
Mustafa, S. S., Vadamalai, K., Bingemann, T. and Ramsey, A. 2020. Efficacy of epinephrine and diphenhydramine
rinses in decreasing local reactions to subcutaneous aeroallergen immunotherapy. Allergy Asthma Proc.
41: 52–58.
Nelson, H. S., Iklé, D. and Buchmeier, A. 1996. Studies of allergen extract stability: the effects of dilution and mixing.
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Nelson, H., Blaiss, M., Nolte, H., Würtz, S. Ø., Andersen, J. S. and Durham, S. R. 2013. Efficacy and safety of the
SQ-standardized grass allergy immunotherapy tablet in mono- and polysensitized subjects. Allergy 68: 252–5.
Nelson, H. S. 2016. Allergen immunotherapy (AIT) for the multiple-pollen sensitive patient. Expert Rev. Clin.
Pharmacol. 9: 1443–1451.
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Nelson, H. S. 2022. Future directions in allergy immunotherapy. Allergy Asthma Proc. 43: xxx.
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in patients with allergic rhinitis. Ann. Allergy Asthma Immunol. 96: 600–605.
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Pajno, G. B., Caminiti, L., Vita, D., Barbrerio, G., Salzano, G., Lombardo, F. et al. 2007. Sublingual immunotherapy
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Roberts, G., Pfaar, O., Akdis, C. A., Ansotegui, I. J., Durham, S. R., Gerth van Wijk, R. et al. 2018. EAACI guidelines
on allergen immunotherapy: allergic rhinoconjunctivitis. Allergy 73: 765–798.
Sapsaprang, S., Boonard, K., Pacharn, P., Srisuwatchari, W., Visisunthorn, N. and Jirapongsananuruk, O. 2020.
Epinephrine-coated syringe for SCIT reduced local reactions: A randomized, double-blind, placebo-controlled
trial. J. Allergy Clin. Immunol. Pract. 8: 1465–1467.
Scadding, G. W., Caldron, M. A., Shamji, M. H., Elfan, A. O., Penagos, M., Dumitru, F. et al. 2017. Effect of 2 years
of treatment with sublingual grass pollen immunotherapy on nasal response to allergen challenge at 3 years
among patients with moderate to severe seasonal allergic rhinitis: The GRASS randomized clinical trial. JAMA
317: 615–625.
Shamji, M. H., Layhadi, J. A., Sharif, H., Penagos, M. and Durham, S. R. 2021. Immunological responses and
biomarkers for allergen-specific immunotherapy against inhaled allergens. JACI Pract. 9: 1769–78.
Stelmach, I., Sobocińska, A., Majak, P., Smejda, K., Jerzyńska, J. and Stelmach, W. 2012. Comparison of the
long-term efficacy of 3- and 5-year house dust mite allergen immunotherapy. Ann. Allergy Asthma Immunol.
109: 274–278.
Tabar, A. I., Arroabarren, E., Echechipía, S., Garcia, B. E., Martin, S. and Alvarez-Puebla, M. J. 2011. Three years
of specific immunotherapy may be sufficient in house dust mite respiratory allergy. J. Allergy Clin. Immunol.
127: 57–63.
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Weber, R. W. 2007. Cross-reactivity of pollen allergens: impact on allergen immunotherapy. Ann. Allergy Asthma
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Wong, P. H., Quinn, J. M., Gomez, R. A. and Webb, C. N. 2017. Systemic reactions to immunotherapy during mountain
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Chapter 10
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Targeted and Biologic Therapeutics for
Allergic and Immunologic Diseases
Bindon, Brittany,
1,#
Zahid, Soombal,
1,#
Chapman, Nicholas2 and Wang, Eileen1,*
Introduction
Targeted and biologic therapeutics have rapidly expanded over the past few decades, revolutionizing
the management and treatment of various disorders. Here, we discuss the targeted therapeutics
approved for several allergic and immunologic disorders as well as promising agents under
investigation. Efficacy, safety and logistical data is outlined to aid clinicians in precision medicine.
Asthma
Asthma is a chronic airway inflammatory disease affecting around 300 million people worldwide.
Up to 10% of adult asthmatics have been reported to suffer from severe asthma, which is associated
with increased morbidity and mortality (Manka and Wechsler 2018). Several biologic therapies have
been approved for use in severe asthma, as seen in Table l. These have dramatically changed the
treatment landscape, providing patients with severe or refractory disease relief from exacerbations
and symptoms as well as improved quality of life (QoL). However, important questions that remain
are their cost-effectiveness, duration of use as well as predictors of response, thus warranting
ongoing studies.
Anti-Immunoglobulin IgE
IgE is responsible for the initiation of Type 1 hypersensitivity reactions involved in the
pathophysiology of many allergic disorders. Omalizumab is a recombinant humanized monoclonal
antibody, which binds to the Cε3 domain of IgE, lowering free IgE levels and downregulating
high-affinity IgE receptors (FcεRI) on basophils and mast cells (Kaplan et al. 2017).
Omalizumab
Efficacy Data
Omalizumab is approved for moderate-to-severe persistent asthma (6 years and older) with
sensitization to perennial aeroallergens and symptoms inadequately controlled on inhaled
1
National Jewish Health and the University of Colorado School of Medicine.
2
St Joseph Hospital, Denver (Colorado).
#
Co-First Authors.
* Corresponding author: wange@njhealth.org
Table 1. Biologics approved for treatment in asthma.
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220 Textbook of Diagnostic and Therapeutic Procedures in Allergy
Mechanism of
Action
Anti-IgE Omalizumab
Anti-IL-5 Mepolizumab
Anti-IL-5Rα Benralizumab
IL-4Rα
(impacts IL-4
and IL-13)
Anti-TSLP Tezepelumab
Table Adapted with permission from Wang, E. and Wechsler, M. E. 2022. A Rational Approach to Compare and Select Biologic Therapeutics in Asthma. Ann. Allergy Asthma Immunol.
(Wang and Wechsler 2022).
Key: FDA: U.S. Food and Drug Administration; OCS: oral corticosteroid; CSU: chronic spontaneous urticaria; EGPA: eosinophilic granulomatosis polyangiitis; HES: hypereosinophilic syndrome; CRSwNP: chronic rhinosinusitis with nasal polyps; A.D.: Atopic dermatitis, OCS: oral corticosteroid; SC subcutaneous; FEV1: forced expiratory volume in one second;
EoE: eosinophilic esophagitis.
Drug Approved
Indications in
the US
2003 Asthma
2016 CSU
2020 CRSwNP
2015 Asthma
2019 EGPA
2020 HES
2021 CRSwNP
Reslizumab
Dupilumab
2016 Asthma ≥ 18 3.0 mg/kg Q4W IV
2018 Asthma ≥ 12 30 mg Q4W
2017 A.D.
2018 Asthma
2019 CRSwNP
2022 EoE
2022 Prurigo
Nodularis
2021 Asthma ≥ 12 210 mg Q4W SC
Age
Approved
for Asthma
(years)
≥ 6 75–375 mg
≥ 6 100 mg
≥ 6 200 mg or 300
Dosing and Frequency Route Phase 3 Clinical Trial Results
(based on
weight, IgE
level and age)
300 mg
(EGPA and
HES)
mg
300 if OCS-
dependent.
Q2W
Q4WSCOce
Home
Q4W SC
Oce
Home (for
> 11 y.o.)
Clinic/
Infusion
center
SC
(x3) →
Q8W
Q2W SC
Oce
Home
Home
Exacerbation
Reduction
ü
ü
ü
ü
ü
ü
Increased
FEV1
Minimal
increase
ü ü
ü ü
ü ü
ü ü
ü
Maintenance OCS Reduction
(Not done prospectively but
post hoc analysis)
*Not assessed in NAVIGATOR
phase 3 RCT. However,
not found to be signicant
in preliminary data from
SOURCE phase 3 RCT
Targeted and Biologic Therapeutics for Allergic and Immunologic Diseases 221
https://t.me/medicina_free
corticosteroids (ICS). Omalizumab dosing is based on body weight and serum total IgE level as
detailed in Table 1. In a pivotal phase 3 randomized control trial (RCT), adult and adolescent patients
with allergic asthma treated with omalizumab had significantly fewer asthma exacerbations, greater
reduction in daily inhaled corticosteroid (ICS) dose, symptoms and improved lung function, as
measured by mean morning peak expiratory flow (PEF) and mean forced expiratory volume in
1 second (or FEV1) compared with placebo (Soler et al. 2001). These results were corroborated in
children with allergic asthma as well (Milgrom et al. 2001). In a pooled analysis of various phase 3
RCTs, treatment with omalizumab led to lower incidences of serious asthma exacerbations requiring
unscheduled outpatient visits, emergency room (ER) treatments and hospitalizations (Corren
et al. 2003).
Special Populations
Asthma morbidity is known to be higher for the inner-city population, which is partly attributed to
the prevalence of allergic sensitization as well as high exposure to indoor allergens. In the ICATA
study, treatment with omalizumab significantly reduced the number of days with asthma symptoms
in inner-city children and young adults as well as the proportion of patients who experienced
exacerbations or who were hospitalized. Additionally, patients treated with omalizumab missed
significantly fewer school days along with significant reductions in seasonal exacerbations
compared with placebo (Busse et al. 2011). Building upon this, the PROSE study found that the
odds of a fall season exacerbation were significantly lower with omalizumab treatment and patients
had a lower risk of respiratory virus-associated exacerbation (Esquivel et al. 2017). Furthermore,
omalizumab was found to decrease the frequency, duration and peak shedding of rhinovirus (RV)
illnesses (Esquivel et al. 2017).
Real-World Studies
In a meta-analysis of 86 real-world observational studies, omalizumab significantly reduced the
annual risk of asthma exacerbations as well as significantly reduced the proportion of patients
receiving oral corticosteroid (OCS) (Bousquet et al. 2021). Omalizumab significantly improved
lung function along with improvement in patient symptom control and QoL. Treatment also led
to decreased health-care resource utilization including hospitalizations, ER visits and unscheduled
physician visits.
Accessible biomarkers to assess responses are clinically pertinent. In the PROSPERO
real-world study, clinical response to omalizumab was not impacted by baseline biomarkers,
including blood eosinophil count (BEC) or fractional exhaled nitric oxide (FeNO) (Casale et al.
2019a). In contrast, RCT found that omalizumab’s efficacy was deemed greatest in high baseline
Type 2 (T2) biomarker subgroups (FeNO, BEC and serum periostin) when compared with the
low-biomarker subgroups (Hanania et al. 2013). Given mixed results, further studies are warranted.
Other Disease Considerations
In addition to United States Food and Drug Administration (FDA) approval for allergic asthma,
chronic spontaneous urticaria (CSU) and chronic sinusitis with nasal polyps, various case studies
and small RCTs have demonstrated omalizumab’s efficacy in off-label use for the treatment of
non-allergic asthma (Garcia et al. 2013) and asthma with chronic obstructive pulmonary disease
(COPD) overlap (Hanania et al. 2019). Additionally, omalizumab has proven beneficial in the
off-label treatment of allergic bronchopulmonary aspergillosis (ABPA) (Li et al. 2017). Multiple
case reports note the use of omalizumab off-label for idiopathic anaphylaxis (Kaminsky et al.
2021) and it has been used to prevent anaphylaxis as well as other associated symptoms in systemic
mastocytosis (Jendoubi et al. 2020). These results, however, were not replicated in a more recent
small RCT (Carter et al. 2021). Additionally, a rapidly expanding area of research is the use of
off-label omalizumab as an add-on therapy for food oral immunotherapy (OIT), though additional
studies are needed (Andorf et al. 2018).
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