Omalizumab - An Overview

Dr. Deval Mistry

 Urticaria
 A dermatological disorder characterized by the sudden appearance of
itchy hives (wheals), angioedema or both1

1. Zuberbier T, et al. Allergy 2014;69:868–87 An Bras Dermatol. 2005;80(6):613-32

Urticaria can be classified based on duration, frequency, and cause

Known causes
(including autoimmune,
Spontaneous infection)

No obvious external
specific trigger
Unknown causes
Chronic
Symptoms daily or
almost daily for ≥6 Chronic spontaneous
weeks
Inducible urticaria
Urticaria
Acute Symptoms induced by
a specific trigger, e.g.
temperature,
Symptoms for
pressure, cholinergic
<6 weeks

Chronic spontaneous urticaria (CSU) can be defined as the spontaneous daily, or almost daily, occurrence
of itchy hives, angioedema or both, lasting for 6 weeks or more

Adapted from: Zuberbier T, et al. Allergy 2014;69:868–87

CSU is a chronic disease whose duration is estimated to be 1–5 years in most
cases1,2

Of the diagnosed CSU patient population:

50% will resolve

20% will resolve 20% will resolve <2% will resolve
within 6 months
within 3 years2 within 5–10 years2 within 25 years2
of onset2

Years since diagnosis

Year 1 Year 2 Year 3 Year 4 Year 5 Year 25

• In very rare cases, CSU can persist for up to 50 years1

1. Maurer M, et al. Allergy 2011;66:317–30;

2. Adapted from: Beltrani VS. Clin Rev Allergy Immunol 2002;23:147–69.

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 Disease activity in CSU should be assessed using the Urticaria Activity Score
(UAS)1,2

• The UAS is a validated daily measure, encompassing hives and itch, to assess urticaria severity
and monitor treatment outcomes1,2

Score Hives (wheals) Score Itch Severity Score (ISS)

0 None 0 None

1 Mild (<20 hives/24 hours) 1 Mild (present, but not annoying or

troublesome)
2 Moderate (20–50 hives/24 hours) 2 Moderate (troublesome, but does not interfere
with normal daily activity or sleep)

3 Intense (>50 hives/24 hours or large 3 Intense (severe itch, which is sufficiently
confluent areas of hives) troublesome to interfere with normal daily
activity or sleep)

Daily UAS (scored from 0 to 6) = sum of daily ISS and hives scores

• 1. Zuberbier T, et al. Allergy 2009;64:1417–26;

2. Mlynek A, et al. Allergy 2008;63:777–80.

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UAS7 is a weekly composite score of the ISS and number of hives score, used to
measure disease activity1

• Weekly ISS is the sum of daily ISS over 7 days (scale 0–21)

• Weekly number of hives score is the sum of the daily number of hives score over 7 days (scale 0–21)

• UAS7 is a composite score of the weekly ISS and weekly number of hives score (scale 0–42)

Sum for 7 days

Itch (intensity) Hives (number)
0  none 0  none
1 = <20 hives Daily UAS7
1  mild
UAS (0–6) (0–42)
2  moderate 2 = 20–50 hives
3  intense 3 = >50 hives
Once daily Once daily

• 1. Zuberbier T, et al. Allergy 2014;69:868–87

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 UAS7 is a measure of CSU severity over 7 days

42

36 UAS7=28–42: severe CSU1 typically with an intense itch and >50 hives over 24 hours
28–42
or large confluent areas of hives2
30

24
UAS7=16–27:* moderate CSU1 typically with a troublesome itch and up to 50 hives
16–27
over 24 hours2
18

12 UAS7=7–15: mild CSU1 typically with a mild itch and fewer than 20 hives over 24
7–15
hours2
6
UAS7=1–6:ǂ well-controlled CSU;1 typically with a mild itch and no hives or fewer
1–6
than 20 hives over 24 hours2
0
0 UAS7=0:ǂ itch- and hive-free over 7 days1

• 1. Stull D, et al. EAACI 2014;

2. Zuberbier T, et al. Allergy 2014;69:868–87.

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EAACI/GA²LEN/EDF/WAO - 2017 Revision and Update
 Other Recommendations
 2nd generation H1-antihistamines > 1st generation H1-
antihistamines
 Recommend against using higher than 4-fold standard
dosed H1-antihistamines
 Recommend against using different H1-antihistamines at
the same time
 Consider a short course of systemic glucocorticosteroids in
patients with an acute exacerbation of CU
 Cannot make a recommendation with respect to montelukast as
add-on treatment in patients with chronic urticaria
unresponsive to H1-antihistamines
 Cannot make a recommendation for or against the combined
use of H1-and H2-antagonists in patients with chronic urticaria
 Cannot make a recommendation with respect to further
treatment options
 EAACI/GA2LEN/EDF/WAO urticaria guidelines

Previous (2009) guidelines1 Updated (2013) guidelines2

Position Omalizumab as Position Omalizumab as a
4th line treatment option 3rd line treatment option

1st line Second generation H1-antihistamine 1st line Second generation H1-antihistamine
If symptoms persist If symptoms persist
after 2 weeks after 2 weeks
Up-dosing (up to 4 licensed dose)§ of Up-dosing (up to 4 licensed dose)§ of
2nd line 2nd line
second generation H1-antihistamine second generation H1-antihistamine
If symptoms persist If symptoms persist
after 1–4 further weeks after 1–4 further weeks
3rd line Add leukotriene antagonist or change nsAH 3rd line Add* Omalizumab,‡ cyclosporin A§ or montelukast§
Exacerbation: systemic corticosteroid (3–7 days) Exacerbation: systemic corticosteroid§ (3–7 days)
If symptoms persist
after 1–4 further weeks
Changes in the 2013 update include:
4th line
Add cyclosporin A,§ H2-antihistamine, dapsone,  H2-antihistamine and dapsone are no longer included
Omalizumab‡  Omalizumab and cyclosporin A have moved to 3rd line
Exacerbation: systemic corticosteroid§ (3–7 days)

*the order of third-line treatments does not reflect preference;

‡Licensed in Europe and the US; §Not licensed for treatment in CSU..

EAACI = European Academy of Allergy and Clinical Immunology; 1. Adapted from Zuberbier T, et al. Allergy 2009;64:1427‒43;
GA2LEN = Global Allergy and Asthma European Network; 2. Zuberbier T, et al. Allergy 2014;69:868–87.
EDF = European Dermatology Forum; WAO = World Allergy Organization.
Consensus Statement : 2011
 Omalizumab
• Humanized, monoclonal, anti-IgE Murine CDRs
(5% of
antibody comprising a human IgG molecule)
framework onto which are
incorporated the complementarity-
determining regions from a murine
anti-IgE antibody IgG1 kappa
human
• 95% IgG1 kappa human framework framework
(95% of
molecule)
• 5% mouse sequence, which is hidden
from the immune system when
omalizumab binds to IgE
 Mechanism of Action
Allergen binding site

IgE

Omalizumab/
FcɛRI receptor
binding site

Trimers Hexamer

Omalizumab
• Binds to free IgE in the blood and interstitial space, forming biologically inactive IgE
complexes - unable to bind to FceRI on the surface of mast cells and basophils , reducing
trigger to mast cell & basophil degranulation & the subsequent inflammatory cascade

• Down regulates IgE receptors

• Reduces mast cell releasability

• Reverses basopenia and improves basophil IgE receptor function

• Gene expression in lesional skin altered to levels seen in non lesional skin
 Pharmacokinetics and Pharmacodynamics
• Absolute bioavailability – 62%

• Peak serum concentrations after an average of 7-8 days

• Linear pharmacokinetics across the dose range of 75 mg to 600 mg given as

single subcutaneous dose

• Maximum suppression of free IgE occurs on day 3 following the first dose

Full prescribing information of Xolair (omalizumab) Novartis Healthcare Private Limited India pack insert dated 16 Jan 2015 based on the international package leaflet (IPL) dated 13 March 2014.
• Total IgE levels in serum increases after the first dose due to the formation of
omalizumab-IgE complexes which have a slower elimination rate compared to free
IgE
• After repeat dosing ,once every 4 weeks at 75 mg up to 300 mg:
average serum total IgE levels at Week 12 are two-to three-fold higher compared
with pre-treatment levels, and total and free IgE remain stable between 12 and 24
weeks of treatment
• After discontinuation of Omalizumab dosing, free IgE levels increases and total IgE
levels decreases towards pre-treatment levels over a 16-week follow-up period

Full prescribing information of Xolair (omalizumab) Novartis Healthcare Private Limited India pack insert dated 16 Jan 2015 based on the international package leaflet (IPL) dated 13 March 2014.
 PRE-INJECTION INVESTIGATIONS
• Complete Blood Count
• Random Blood Glucose
• Renal Function Test
• Liver Function Test
• Urine Routine and Microbiology
• Chest X-ray
• ECG
 DOSAGE
• Omalizumab 300 mg by subcutaneous injection every 4 weeks -
dosage not dependent on serum IgE or body weight
 RECONSTITUTION & ADMINISTRATION
1. Before reconstitution, determine the number of vials that will need to
be reconstituted (each vial delivers 150 mg of Omalizumab in 1.2 mL)
2. Draw 1.2 mL of Sterile Water for Injection (SWFI) into a 3 mL syringe
equipped with a 1 inch, 18-gauge needle
3. Keeping the vial upright, inject the SWFI into the vial,gently swirl the
upright vial for approximately 1 minute to evenly wet the powder
4. Gently swirl the vial for 5 to 10 seconds approximately every 5 minutes
in order to dissolve any remaining solids. Do not use if the contents of
the vial do not dissolve completely by 40 minutes
5. After reconstitution, Omalizumab solution is somewhat viscous and
will appear clear or slightly opalescent
6. Using a new 3 mL syringe equipped with a 1-inch, 18-gauge needle, insert the needle into
the inverted vial. Position the needle tip at the very bottom of the solution in the vial
stopper when drawing the solution into the syringe
7. Replace the 18-gauge needle with a 25-gauge needle for subcutaneous injection

• The injection may take 5-10 seconds to administer as the solution is slightly viscous
• Do not administer more than 150 mg(contents of one vial) per injection site
• Use the Omalizumab solution within 8 hours following reconstitution when stored in
the vial at 2 to 8ºC, or within 4 hours of reconstitution when stored at room temp
• Reconstituted Omalizumab vials should be protected from sunlight
 INDICATIONS

• Chronic Idiopathic Urticaria (CIU): FDA Approved

Adults and adolescents 12 years of age and older with chronic idiopathic
urticaria who remain symptomatic despite H1 antihistamine treatment

• Omalizumab is not indicated for treatment of other forms of urticaria

• Pregnancy Category B

• Off Label Indications - Atopic dermatitis1, Systemic mastocytosis2, Bullous Urticaria3

• Contraindications - Hypersensitivity to Omalizumab or any ingredient

1. Park S-Y, Choi M-R, Na J-I, Youn S-W, Park K-C, Huh C-H. Recalcitrant Atopic Dermatitis Treated with Omalizumab. Annals of Dermatology. 2010;22(3):349-352. doi:10.5021/ad.2010.22.3.349.

2. Douglass, J. A., Carroll, K., Voskamp, A., Bourke, P., Wei, A. and O’Hehir, R. E. (2010), Omalizumab is effective in treating systemic mastocytosis in a nonatopic patient. Allergy, 65: 926–927.
doi:10.1111/j.1398-9995.2009.02259

3. Successful treatment of a bullous urticaria with omalizumab.Ozturk AB1, Kocaturk E2, Ozturk E3.PMID: 24957115 DOI: 10.2332/allergolint.14-LE-0699
 WARNINGS AND PRECAUTIONS
• Anaphylaxis
• Malignancy: breast, non-melanoma skin, prostate, melanoma and
parotid
• Acute Asthma: i.e.acute bronchospasm or status asthmaticus
• Corticosteroid Reduction: Do not abruptly discontinue
corticosteroids upon initiation of Omalizumab therapy
• Worsening pulmonary symptoms- flu like symptoms
• Chest tightness, tachycardia
ADVERSE REACTIONS
• Anaphylaxis
• Nausea
• Nasopharyngitis and Sinusitis
• Headache and Fatigue
• Fever and Arthralgia
• Local site reactions : Swelling,
bruising, itching, pain,
urticaria
 RESPONDERS
• Fast responders - within 4–6 weeks
• Slow responders - respond more gradually by weeks 12–16
• Good response - stable UAS7=0, UAS7≤6, ≥90% improvement in UAS7, or simply no itch or
hives (by clinical judgement)
• Partial response - a mild and unstable reduction in the UAS7 vs. baseline (without reaching
UAS7≤6)
• Based on the UAS7 and clinical assessment, non-response could be defined as no change or
increased disease activity compared with the baseline

A. M. Gimienez-Arnau,1* E. Toubi,2 A. M. Marsland,3 M. Maurer4.Clinical management of urticaria using omalizumab: the first licensed biological therapy available for chronic spontaneous
urticaria. JEADV 2016, 30 (Suppl. 5), 25–32.
 Three important landmark studies on the use of omalizumab in CSU - ASTERIA-I, ASTERIA-II,
GLACIAL.
 A total of 733 patients having CSU received omalizumab, and it was found to be effective and safe in
the dose of 300 mg 4 weekly injections (subcutaneous) - reduction in itching and hives with
improvement in DLQI
 In 24 months follow-up study, of the 16 patients with severe CSU using fixed dose omalizumab (150
mg 2–4 weekly), 10 patients (62%) had remission after the first injection of omalizumab, and two
patients discontinued therapy. Of the 14 patients, four patients remained in remission for over 9
months after the last injection, and seven patients continued to be in remission with continuing
maintenance therapy.
 In another study, 30 patients with treatment-resistant CSU being treated with omalizumab were
followed for up to 4 years, with 15 patients completing 4 years treatment.
 Omalizumab was a safe and effective alternative to corticosteroid for refractory urticaria patients. It
is equally effective and safe for long-term use up to 4 years.

Godse K, Rajagopalan M, Girdhar M, Kandhari S, Shah B, Chhajed PN, Tahiliani S, Krupa Shankar D S, Somani V, Zawar V. Position statement for the use of omalizumab in the management
of chronic spontaneous urticaria in Indian patients. Indian Dermatol Online J 2016;7:6-11
 Efficacy & safety in Indian patients
- Published data in 5 CSU Indian patients:

- Significant improvement in all the patients, with reduction in UAS & need of antihistamines. At
the end of 4th months, two patients were free from symptoms and other three required
antihistamine to control their symptoms.

- Side effects were recorded in two patients in the form of headache and fatigue.

Godse et al, Indian J Dermatol. 2011 Jul-Aug; 56(4): 444.

 Omalizumab is approved in adults and adolescents ≥12 years of age with CSU refractory to standard
of care by the Health authority of India. Omalizumab is used as an add-on to antihistamine therapy
and is currently the only licensed therapy for refractory CSU
 Assessment of the severity of CSU to be done using UAS-7 score
 Serum IgE measurement is not needed before the start of omalizumab therapy for CSU
 It is recommended as the third-line therapy for management of CSU by EAACI/GA2LEN/EDF/WAO
2013 guidelines. The Indian consensus recommends omalizumab as the fourth-line therapy
 Omalizumab should only be administered in a setting where the appropriate medications and
equipment are available to respond to an episode of anaphylaxis
 Recommended dose and best response are seen with 300 mg subcutaneous injection once in 4
weeks. Some patients may respond to 150 mg once in 4 weeks and can be tried as per the discretion
of treating dermatologist. Because the solution is slightly viscous, the injection may take 5–10 s to
administer
 Body weight measurement is not required for calculating the dose of omalizumab
 Ice compress may be applied at site of injection to minimize local reactions
 All patients administered omalizumab to be observed for 2 h after dosage for any allergic reactions
 Dose of omalizumab in patients with hepatic/renal compromised status may remain same (i.e., 300
mg once every 4 weeks)
 Omalizumab should only be used during pregnancy if clearly needed. Caution should be exercised
when administering omalizumab to a nursing woman.
 Treatment duration for omalizumab is at the discretion of the treating dermatologist.
 Clinical trial experience for omalizumab is up to 24 weeks (6 months). Real-world data are suggestive
of duration of therapy up to 2–4 years with longer remission up to 9 months.
 Some patients may become refractory and discontinue therapy.