Allergen Immunotherapy and Asthma

Linda Cox, MD, FAAAI

ASCIA 2013 Meeting

Allergen Immunotherapy and Asthma

Overview: burden/prevalence of asthma and allergic disease

Allergen immunotherapy and asthma: is it effective?

SCIT and SLIT efficacy

AIT and asthma safety

AIT as a disease –modifying treatment; prevention, duration

The Burden & Prevalence of Allergic disease: Key Points

• Allergic rhinitis is one of the most common pediatric & adult chronic diseases

• Allergic rhinitis is a risk factor for asthma

• Up to 40% of allergic rhinitis patients will develop asthma

• Asthma is one of the most common and costly chronic pediatric illnesses

• Asthma and allergy medications only control symptoms

• Allergen immunotherapy is currently the only disease modifying treatment for allergic disease

• Disease modification may translate into significant cost-savings 2º to reduced medication use, co-morbidillnesses, progression of disease, etc.

World Health Organization survey regarding asthma Doctor –diagnosed asthma 4.5%

Current World Population Of 7 Billion Translates To 315 Million Individuals With Asthma.

The prevalence of clinical asthma varied widely amongst the 70 participating countries, ranging from 1.0% in Vietnam to 21.5% in Australia, who reported the highest rate of doctor diagnosed, clinical/treated asthma, and wheezing

To et al Global asthma prevalence in adults: findings from the cross-sectional world health survey. BMC public health. 2012;12:204.

0

10

20

30

40

50

60

70

80

1 2 3 4 5 6 7 8 9 10 11 12 13

Age (years)

Prevalence of current wheeze from birth to age 13 years in children with any wheezing episode at school age (5–7 years),

Illi S, et al. Lancet 2006

Non-atopic n=59

Atopic n=94

Sensitisztion to perennial allergens developing in the fi rst 3 years of life was associated with a loss of lung function at school age. 90% non-atopic wheeze

Perennial allergen sensitization early in life and chronic asthma in children: a birth cohort study

Pre

va

len

ce

%

Growing out of “asthma”

A Longitudinal, Population-Based, Cohort Study of Childhood Asthma Followed to Adulthood

Purpose: To identify risk factors for persistence and relapse of asthma

Design: Assessed 1139 children from age 9 to 26 yrs with questionnaires, PFT, bronchial challenge and allergy testing

• Seen every 2 yrs, PFT at 9,11,13,15,21 years

• Skin test 13 & 21years

• 613 with complete respiratory data included in analysis

Seare et al, NEJM 2003; 349:1414-1422

Seare, M et al NEJM 2003; 349:1414-1422

613 Children Followed From Age 9 To 26 Yrs 75% Reported Wheezing On At Least One Occasion And

51% Wheezed > One Occasion

Sensitization to house dust mites predicted the persistence of wheezing (OR,2.41; P=0.001) and relapse (OR, 2.18; P=0.01),

Asthma burden of disease economic reality

US: “Asthma rates and associated costs have increased dramatically over the last thirty years.” 1

• Asthma prevalence increased from 7.3% in 2001 to 8.4% in 2010, ~25.7 million2

• Estimated total direct and indirect costs to society was $56 billion in 2007

• ED and hospitalization ~58% and 64% of total direct costs

• Florida:1

• 2000 - 10: hospital costs more than tripled-$210.8 million to $748.5 million which was a 255% increase,

1. www.doh.state.fl.us/.../medicine/Asthma/FinancialBurdenReport.pdf‎ 2. Akinbami et al Trends in asthma prevalence, health care use, and mortality in the US, 2001–2010. NCHS data brief, no 94.

Florida Asthma Stats

• From 2000 to 2005 ED costs doubled $102.3 million to $204.1 million represents a 99.6% increase

• Largest increase in total charges (and total visits) occurred among those paid for by Medicare or Medicaid (i.e., government insurer.)

Florida Asthma Coalition 36 Measures – Only One Addresses Triggers and this does not specify allergen trigger

Where Does AIT Fit in the Guidelines for Allergen Immunotherapy for Asthma?

ARIA recommendations 2010:

• SCIT: conditional recommendation in allergic asthma

(moderate quality evidence)

• SLIT: conditional recommendation in allergic asthma

(low quality evidence)

GINA report 2012:

• Immunotherapy should be considered only after strict

environmental avoidance and pharmacological intervention,

including ICS

• Immunotherapy is not listed in GINA treatment steps for

achieving control

Brożek et al. ARIA revision 2010. JACI 2010;126:466-76

GINA global strategy for asthma management and prevention: updated 2012

16 Partridge et al BMC pulmonary medicine. 2006;6:13.

Compliance in Asthma is a major concern

70% of patients adjust themselves their medication

• 3415 adults with asthma in 11 countries prescribed regular maintenance therapy,

• 74% of patients used short-acting β2-agonists daily and

• 51% were classified by ACT as having uncontrolled asthma.

• Even patients with well-controlled asthma reported an average of 6worsenings/year

EARLY TREATMENT DOES NOT PREVENT PROGRESSION OR HAVE SUSTAINED EFFECT: PHARMACOTHERAPY IS NOT DISEASE MODIFYING

In preschool children at high risk for asthma, 2 years of ICS did not change the development of asthma symptoms or lung function during a third, treatment-free year.1

CAMP at 4.8 year posttrial f/u no difference in lung function or asthma control seen in ICS vs placebo but still significant decreased mean height (1.1 cm)2

1.Guilbert N Engl J Med 2006; 354 2. Strunk J Pediatr. 2009;154(5):682-7.

PATIENTS PERSPECTIVE ON ALLERGY MEDICATIONS PHARMACOTHERAPY NOT DISEASE MODIFYING OR SATIFACTORY= UNMET NEED

66% of patients who requested an allergy medication change due to dissatisfaction did so because of lack of efficacy

The majority of patients reported that the effects of their medication wore off over time

Nearly a third of patients stopped taking their nasal allergy medication because it did not provide 24-hour relief

Allergies in America Web site. http://www.myallergiesinamerica.com. Accessed September 3, 2007.

According to Allergies in America™, a Survey of

2500 Nasal Allergy Sufferers…

3.3

3.4

4

4.3

4.3

5

3

2.7

2.1

3.4

3.4

5.3

0 1 2 3 4 5 6

Risk of Anaphylaxis

Side Effects

Limited Efficacy

Cost of Therapy

"Needle Phobia"

Patient Concern/Lack ofCommitment on the Need for

Frequent Office Visits

Allergists (n=46)

PCPs (n=46)

Allergen Immunotherapy and Asthma: the controversy

• “Allergen specific immunotherapy has long been a controversial treatment for asthma. The recommendations of professional bodies have ranged from cautious acceptance to outright dismissal.” 1

• ‘It is difficult to compare results from the various studies of IT because of the large number of variations in the clinical trial protocols. Given the heterogeneity of IT clinical trials as a group, it is not surprising that variable results occur. The use of multiple studies in a meta-analysis with its underlying assumption of homogeneity is problematic.’2

1. Abramson ,Allergen immunotherapy for asthma. Cochrane Database Syst Rev 2003

2. Portnoy Ann Allergy Asthma Immunol 2001;87

Is allergen immunotherapy effective in asthma? A meta-analysis of randomized controlled trials

• A meta-analysis of all 20 published prospective, randomized, PC trials of immunotherapy for asthma between 1954-1990

• These were statistically significant improvement in symptoms, medication use, and BHR.

• Mean improvement in FEV1 of 0.71 (CI 0.43-1.00) corresponding to an average FEV1 increase of 7.1%.

Symptomatic improvement

Medication reduction

Decrease in Bronchial Hyperresponsiveness

Odds ratio 3.2 Odds ratio 4.2 Odds ratio 6.8 Confidence interval (2.2-4.9)

Confidence interval (2.2-7.9)

Confidence interval (3.8-12)

Abramson et al. Am J Respir Crit Care Med; 1995 151(4):969-74

The Many AIT Meta-analyses: Symptoms

Burks, et al. Update on allergy immunotherapyAAAAI/EAACI /PRACTALL consensus report. J Allergy Clin Immunol. 2013 Mar 13

SMD=Standardized Mean Difference is the difference of the means of both treatment arms divided by the pooled standard deviation.

Allergen Immunotherapy For Asthma Cochrane Database Systemic Review: 2010

• 88 trials between 1954-2005 with a total of 3,459 with asthma, 13 new trials)

– 42 trials of immunotherapy for house mite allergy

– 27 pollen allergy trials

– 10 animal dander allergy trials*

– 2 Cladosporium mould allergy*

– 1 latex*

– 6 trials of multiple allergens*

• Concealment of allocation was assessed as clearly adequate in only 16 of these trials.

• Significant heterogeneity was present in a number of comparisons.*

Abramson et al.,. Allergen immunotherapy for asthma Cochrane Database Syst Rev. 2010;8:CD001186.

*no change from 20003 update

Allergen Immunotherapy For Asthma Cochrane Database Systemic Review: 2010

Significant improvement in asthma symptom scores (SMD -0.59, CI-0.83 to -0.35)

Immunotherapy significantly reduced allergen specific BHR, with some reduction in non-specific BHR as well.

No consistent effect on lung function

Necessary to treat (NNT)

3 (CI 3 to 5) patients with SIT to avoid one deterioration in asthma symptoms.

4 (CI 34 to 6) patients with SCIT to avoid one requiring increased medication.

One systemic reaction for every 9 treated

Meta-analysis: plotting the data Forest plot: trying to see the wood and the trees

Forest plots show the information from the individual studies used in meta-analysis at a glance which are shown as squares centred on the point estimate of the result of each study.

Horizontal line runs through the square to show its 95% confidence interval.

Show the amount of variation between the studies and an estimate of the overall result

The diamond point at the bottom represents the pooled point estimate, and its horizontal tips represent the confidence interval.

Significance is achieved if the diamond is clear of the line of no

effect.

Lewis, Forest plots: trying to see the wood and the trees BMJ 2001;322:1479-1480

.

Size effect

Poor > -0.20

Medium = 0.50

High < -0.80

Heterogeneity

I2 > 50% significant

Standardised Mean

Difference (SMD) Outcome: Asthma medication score

-0.61

Outcome: Asthma Medication Score

SCIT versus placebo Lung Function

SLIT Placebo

FEV

Non specific

BHR

Specific

BHR

-0.11

SCIT Allergen Specific Bronchial Hyperresponsiveness

Heterogeneity: I2 =0.0%

Dust mite

All allergens: 5 pollen, 6 animal , 2 other

Calamita et al, Efficacy of SLIT in asthma: systematic review of randomized-clinical trials using the Cochrane Collaboration method. Allergy. 2006;61(10):1162-72.

Efficacy of SLIT systematic review of randomized-clinical trials using the Cochrane Collaboration method in

asthma:

Using the above selection method, 25 studies with 1706 patients were included in this meta-analysis (10 specifically on children)

HDM : 8 studies, Pollen : 14, Mixture : 2, Latex : 1

SLIT Meta-Analysis of Asthmatic Symptom Scores

-0.38 [-0.79, 0.03] I2= 63.9%

SLIT: Meta-analysis of Allergic Symptoms Group (Asthma, Rhinitis,

Conjunctivitis, Etc…)

-1.18 [-1.93, -0.43] I2=89.4%

SLIT and Asthma Meta-Analysis

Conclusions:

SLIT is beneficial for asthma treatment albeit the magnitude of the effect is not very large.

Moreover, it is a safe alternative to the subcutaneous route.

More RCT with standardization of symptom scores and medications are needed in order to contribute further to this subject.

Calamitra et al., Allergy 2006;61: 1162-1172

SCIT and SLIT for Asthma Systematic Reviews

Comparison of the systematic reviews of sublingual and subcutaneous immunotherapy

Immunotherapy Route

Asthma symptoms scores

SMD (95% CI)

Asthma medication scores SMD (95% CI)

Subcutaneous1 -0.72

[-0.99, -0.33]

-0.90 [-1.13,-0.40]

Sublingual2 -0.38

[-0.79, 0.03]

-0.91 [-1.94, 0.12]

SMD=standardized mean difference, CI= confidence interval

1. Abramson et al. Allergen immunotherapy for asthma. Cochrane Database Syst Rev 2003:CD001186. 2.Calamita et.al,. Efficacy of sublingual immunotherapy in asthma: systematic review of randomized-clinical trials using the Cochrane Collaboration method. 2006:1162-72

Effectiveness of SLIT vs. SCIT for ARC and Asthma: A Systematic Review

• MEDLINE, Embase, and Cochrane databases were searched through December 21, 2012

• Evidence report commissioned by the US Agency for Healthcare Research and Quality, GRADE methodology

• 8 RCT comparing SLIT & SCIT in managing allergic asthma and ARC were reported in 4 and 6 clinical trials, respectively.

Chelladurai et al, Journal of Allergy and Clinical Immunology: In Practice. 2013;1(4):361-9. 38

Effectiveness of Subcutaneous SLIT vs. SCIT for the Treatment of ARC and Asthma: A Systematic Review

• Low-grade evidence supports greater effectiveness of SCIT than SLIT:

– asthma symptom reduction

– reducing a combined measure of rhinitis symptoms and medication use.

• Moderate-grade evidence supports greater effectiveness of SCIT than SLIT for nasal and/or eye symptom reduction.

• Safety: All 8 trials reported on adverse events with an episode of anaphylaxis reported in a child treated with SCIT.

Chelladurai et al, Journal of Allergy and Clinical Immunology: In Practice. 2013;1(4):361-9. 39

Subjects: Prospective controlled study of 210 children with asthma referred to the pediatric allergy clinic of between 1953- 1955.

Tested to multiple inhalants: pollens, cat, horse, dust, molds, etc.

Randomly assigned to one of 4 groups: saline, or extract mixtures at: 10-7 , 1/5,000 or “highest tolerated up to 1/250 w/v concentration of each allergen to which they had a positive skin test.

Assessed for presence asthma at age 16 years (N=131) . Diagnosis determined by mothers’ diary and clinic assessment of a ‘blinded’ allergist

Johnstone DE, Dutton A, Pediatrics 1968l42:793-802

Dose-response Effect On Persistence of Asthma

Dose-dependent response in terms of presence of asthma

Authors’ conclusions: Allergen immunotherapy is clinically effective in children with asthma

when administered as a multiple allergen mix to multiply sensitized patients.

It is dose-dependent with the highest tolerated dose resulting in maximum efficacy

Johnstone DE, Dutton A, Pediatrics 1968l42:793-802

“Free of Asthma”

Dose group After 4 years of SIT Age 16 year –end of SIT

Placebo and lowest dose

18% 22%

1/5,000 w/v 58% 66%

1/250 w/v or ”highest tolerated”

81% 78%

Multiallergen Immunotherapy for Asthma In Allergic Children.

Methods: DBPC multiple-allergen immunotherapy in 121 allergic children with moderate-to-severe, perennial asthma randomized after 1 year of observation and stabilization to SCIT with up to 7 allergens or placebo injections.

Medications were adjusted every 2-3 weeks on the basis of PEFR and symptoms the previous 14 days.

Principal outcome was the daily medication scores.

Study was essentially asking at least 2 questions: Is multiallergen SCIT effective ? & Is effective as add-on to optimal pharmocotherapy & environmental control

measures?

Adkinson F, et al., N Engl J Med 1997; 336

Efficacy of Multiallergen SCIT in Asthmatic Children Not Demonstrated BUT

Results: No difference between groups in medication score (1° outcome), use of medical care, symptoms, median PC20 or PEFR- but a trend toward favoring SCIT in 8/10 outcomes

Subgroup analysis - approached statistical significance in favor of SCIT in

– Younger age (8.5 years; p =0.02)

– Mild asthma (medication score, 5; p= 0.19 and no ICS use)

• Authors suggested ““future investigations should focus on the potential prophylactic use of immunotherapy in children with allergic rhinitis, who are at high risk for asthma, or in highly allergic children with the recent onset of mild asthma.”

Adkinson et al., N Engl J Med 1997; 336

Effect of SCIT added to pharmacologic treatment and allergen avoidance in HDM asthmatic patients

Method: DBPC study of 72 HDM randomized to SCIT or placebo after an observational year of pharmacotherapy & allergen avoidance. Maintenance 6 mcg (Der 1 + Der 2) Q 3 weeks.

Results: SCIT was associated with

Significant decrease in # of subjects needing rescue β-agonist

Increase in AM & PM PEFR

Reduced dust mite skin test reactivity

No significant effects on the cumulative dose of ICS, asthma symptoms , lung volumes, or methacholine BHR

Maestrelli et al, J Allergy Clin Immunol 2004;113:643-9.

SLIT HDM Allergic Asthma in Children

Method: 97 mild to moderate asthmatic children aged 6-12 years monosensitized to DM randomized to placebo or SLIT for 24 weeks

Cumulative dose: 1.7 mg of Der.p. and 3.0 mg of Der.f. ~26

mcg daily or 783 mcg monthly of mixed mites

Results:

Statistically significant difference between 2 groups:

Daily, nighttime, and daytime asthmatic scores

Improved FVC, FEV1, and PEF as compared to baseline

No differences were found in SPT, total IgE and specific IgE

Tolerance with was good with few minor adverse events reported

Niu et al., Respir Med 2006; 100:1374-83.

SLIT for HDM-allergic Asthma

There was statistically significant difference between the two groups in the analysis of daily and nighttime asthmatic scores after 24 weeks of treatment

Niu et al., Respir Med 2006; 100:1374-83.

Comparison of asthma scores (mean ± SD) before and after 24-week treatment between SLIT and placebo group.

daily nighttime

Changes of daily asthma scores (mean ± SD) in SLIT and placebo groups throughout the study period

SLIT for HDM-allergic Asthma in Children

Improvement of asthma symptoms gradually over time in the SLIT group. Placebo group had almost the same asthma score at the endpoint as baseline

Niu et al., Respir Med 2006; 100:1374-83.

SLIT for Seasonal Asthma in Children

Method: 39 children aged 3-16 years with seasonal allergic asthma randomized to placebo or SLIT over 2 successive grass-pollen season

• Requiring at least 200 μg of inhaled beclomethasone (or

equivalent) daily

• Results:

• “Substantial reduction” in the asthma symptom-medication

score (p = .04) in the SLIT compared with placebo group.

• After the first and second pollen seasons, there were statistically

significant differences between the 2 treatment groups for

bronchial allergen reactivity

• No difference in highest FENO value

Roberts et al . J Allergy Clin Immunol. 2006;117(2):263-8.

Fig 3

Seasonal Asthma in Children

Immunotherapy was shown to lead to substantial reductions in reactivity to grass pollen in the lungs

Roberts et al . J Allergy Clin Immunol. 2006;117(2):263-8

Grass-pollenBHR

Allergen concentration producing a 20% FEV1 decrease

Allergy Immunotherapy Safety

If 9 patients were treated with SCIT, expect 1 to develop a SR of any severity

AAAAI/ACAAI Surveillance Study of SCIT Safety: 10.2 SRs per 10,000 injection visits (0.1% for all 3 years)

About 8 million injections visits per year

Per injection SR rate & number (%) practices reporting1

• Grade 1 mild SR:

– 1 per 1,287 (.07% injection visits)

– 613 (76%) practices

• Grade 2 moderate SR:

– 1 per 4,166 (.02% injection visits)

– 436 (54%) practices

• Grade 3 severe SR:

– 1 per 30,566 (.003%)

– 144 (18%) practices

Grade 1 Mild

Grade 2 Moderate

Grade 3 Severe

6,293

1,944

265

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ys

tem

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ea

cti

on

s

Epstein et al Annals of Allergy, Asthma & Immunology. 2013;110(4):274-8.

74%

23%

3%

Worse Case Scenario Subcutaneous Immunotherapy Fatalities

3 surveys of AAAAI members on immunotherapy fatalities spanning time period between 1945-2001

SLIT Safety in Published Literature

• SLIT appears to be better tolerated than SCIT.

• No reports of SLIT-related fatalities to date in an estimated one billion doses

• Majority of SLIT AEs are local reactions in the mouth and throat are common at the beginning of treatment, but resolve within a few days or weeks without any medication intervention

• Dose-response relationship with AEs in some studies

• No apparent relationship with updosing schedule and AEs

• Several large (N>300 patients) grass-pollen tablet studies

demonstrate good safety profile with no updosing

• Few reported cases of anaphylaxis (at least 11)*

Calderon et al . Allergy. 2012 Mar;67(3):302-11.

Sublingual Immunotherapy Safety Summary

• SLIT should only be prescribed by physicians with appropriate allergy training and expertise.

• Specific instructions should be provided to patients regarding the management of adverse reactions, unplanned interruptions in treatment and situations when SLIT should be withheld.

• Risk factors for the occurrence of SLIT severe adverse events have not yet been established. Although there is some suggestion that there may be increased risk in patients who have had prior SCIT systemic reactions.

• A uniform classification system for grading for AIT systemic reactions2 and SLIT LR has been developed by WAO3

1. Canonica et al, Sublingual Immunotherapy: WAO Position Paper Update. 2013 in progress 2. Cox L, et al, J Allergy Clin Immunol. 2010 Mar;125(3):569-74, 74 e1-74 e7 3. Passalacqua. Grading local side effects of sublingual immunotherapy: speaking the same language. Submitted for

publication

Characteristics Of The Slit-induced Anaphylaxis Reported In Literature

Author, year Sex (age)

Allergen (producer)

Phase Onset Description Epinephrine

De Groot, 2009

M (13) Grass (Grazax, ALK-Abellò)

First dose 15 min Generalized urticaria, swelling of tongue

NO

De Groot, 2009

F (27) Grass (Grazax, ALK-Abellò)

First dose 5 min Abdominal cramps, asthma, generalized itching, hypotension

YES

Blazowski, 2008

F (16) HDM (Staloral, Stallergenes)

Maintenance overdose (60 drops)

10 min Hypotension-collapse, flushing, urticaria

YES

Eifan, 2008 F (11) dust mite + grass pollen mix (Stallergenes)

Maintenance.

3 min Abdominal pain, chest pain, fever, nausea

Not specified

Dunski, 2006 F (31) Alternaria, cat, dog grass, ragweed, (Greer)

2nd day of updosing

5 min Angioedema, dizziness, dyspnea, generalized itching

NO

Antico, 2006 F (36) Latex End of rush buildup

10 min Asthma, generalized urticaria

Not specified

Speaking the Same Language in Terms of AIT Safety Reporting

1. Cox et al, J Allergy Clin Immunol 2010;125:569-74 2. Passalacqua et al, J Allergy Clin Immunol. 2013: in press

1

2

Measures to Improve Safety Premedication Antihistamines

– Studies with RIT & cluster suggest decreased incidence of local and SRs.

– Conventional IT:

• One DBPC study found premedication with fexofenadine reduced # of severe SRs, ↑ number of pts who reached TMD &↓ time to TMD1

Leukotriene receptor antagonist

– Anecdotal reports of reductions in SR rates . One DBPC study demonstrated ↓ LLR during venom RIT with moneleukast2

1.Ohashi et al, Ann Allergy Asthma Immunol 2006; 96 2. Wohrl et al., Int Arch Allergy Immunol 2007;144:137-42

Effect of 16 week pretreatment with omalizumab on the tolerability of AIT in moderate persistent allergic asthma inadequately controlled

with ICS

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6

2

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2

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5

10

15

20

25

30

Grade 1 (Skin) Grade 2 (GI) Grade 3

(Resp)

Grade 4 (CV)

Nu

mb

er

of

Pa

tie

nts

Omalizumab PlaceboN=17 N=32

Severity of First Systemic Allergic Reaction Patients who experienced SR: omalizumab 13.5%, placebo 26.2%

P= 0.017

Massanari et al, J Allergy Clin Immunol. 2010;125(2):383-9

AIT and Asthma Safety

SCIT incidence of SR ~ 0.1% of injections

Poorly controlled/symptomatic asthma identified risk factor for SCIT severe AE

SLIT appears to have safer profile

Majority of studies have been done in AR ± mild-to-moderate asthma and no studies in severe asthma

Risk factors for SLIT severe AE have not yet been established but ? increased risk in prior SCIT SR patients

Unmet need per WAO SLIT PPU

The safety of SLIT in moderate to severe asthmatics.

Are there are specific precautions/instructions for asthma patients before taking SLIT

Duration of Allergy Immunotherapy Efficacy

AIT

Duration of allergen immunotherapy in respiratory allergy: when is enough, enough?

OBJECTIVES: To investigate the duration of effective SCIT reported in

the published literature.

RESULTS: The rate of relapse after discontinuing SCIT ranges from 0% to 55% of patients . The length of the SCIT and allergen type (ie, perennial vs seasonal) may be variables that affect the duration of clinical remission after cessation of SCIT.

CONCLUSION: Until specific tests or clinical markers are identified that will clearly distinguish between patients who will relapse from those who will remain in long-term clinical remission after discontinuing effective allergen immunotherapy, the decision to continue or stop immunotherapy must be individualized.

Cox L ,Cohn J, Ann Allergy Asthma Immunol 2007; 98:416-426

Long-term follow-up of patients treated with a three-year course of cat or dog immunotherapy

• A 5-year follow-up study was conducted to investigate the duration of the effects of a 3-year course of immunotherapy with standardized cat or dog extracts in 32 children and adults with asthma caused by animal dander.

Clinical Allergen-BHR NS-BHR

Hedlin et al J Allergy Clin Immunol. 1995;96(6 Pt 1):879-85. Table from Cox L ,Cohn J, Ann Allergy Asthma Immunol 2007; 98:416-426

0

0.2

0.4

0.6

0.8

1

2007 2008 2009 2010

Placebo

300IR 2M

300IR 4M

AC

S (

ad

juste

d m

ea

ns)

- 23% - 15%

- 29% - 29%

- 27% - 26%

66

En

d o

f tr

ea

tme

nt

- 34% - 32%

0.0067 < .0001 < .0001 < .0001 < .0001 0.0002 0.0057 0.0060 p value

ANCOVA – (FAS)

Long-term Clinical Efficacy 300 IR grass SLIT tablets Discontinuous Treatment 2 vs. 4 months Before Season

Average Combined Score (ACS): Worst Pollen Period - years 1 to 4

The Average Combined Score results are consistent with the Average Adjusted Symptom Score throughout the 4 years at worst pollen period.

EAACI 2011 Annual Congress presentation Professor Sabina Rak-provided with permission Robert Zeldin, MD Didier et al, J Allergy Clin Immunol. 2011 Sep;128(3):559-66

Immunotherapy with a standardized dust mite Duration of the efficacy of immunotherapy after cessation.

Study design: 40 asthmatic received SIT with DPT for 12 to 96 months followed for 3 years after discontinuation

55% of pts relapsed. Relapse defined as return of asthma

± rhinitis or impaired PFT

Duration of efficacy related to

Duration of immunotherapy (P<0.04)

52% of pts treated >36 months no relapse vs. 38% no relapse in <35 month treatment group

Decrease in skin test reactivity (P<0.003)

Most pts who did not relapse had ↓ed STR vs. most who relapsed had no change

• Des Roches et al. Allergy 1996; 51: 430-4

Optimal Duration for Sublingual Immunotherapy

Methods: In this prospective open controlled study we followed up patients with respiratory allergy who were monosensitized to mites for 15 years.

• 4 groups receiving drug therapy alone or SLIT for 3, 4, or 5 years.

• Clinical scores, skin sensitizations, MCH, and nasal eosinophila evaluated yearly during the winter months.

• Clinical effect was considered to persist until clinical scores remained at less than 50% of the baseline value, and then patients underwent another course of SLIT.

Marogna et al. J Allergy Clin Immunol. 2010;126(5):969-75

4-year duration of SLIT is the optimal choice

CONCLUSION: “.. it can be suggested that a 4-year duration of SLIT is the optimal choice because it induces a long-lasting clinical improvement similar to that seen with a 5-year course and greater than that of a 3-year vaccination.”

Marogna et al. J Allergy Clin Immunol. 2010;126(5):969-75

New sensitizations in all control subjects Less than 25% SLIT patients: 21%-3yr, 12%-4yr , 11%-5 yr

SLIT for 4 or 5 years= 8 years of control.

Preventing the progression of the allergic disease i.e. the allergic march

Preventive Allergy Treatment (PAT) Study: Multi-center prospective

European study

Objective: to determine if SCIT can prevent the development of asthma in 205 children, ages 6-14, with mod-severe allergic rhinitis:

randomized to either SIT (birch and/grass) or an open control group for 3 yrs.

asthma was diagnosed as recurrence of at least 2 of the following 3 symptoms within the previous 12 months

Cough Wheeze Shortness of breath

SCIT Reduces Risk of Developing Asthma End of treatment1 and 5-year2 & 10-year3 follow-up two (n=142)2 &

seven yrs (n=117)2after SCIT discontinuation

Odds-ratio: 3 years= 2.52 (1.3 – 5.1) 5 year= 2.68 (1.3 – 5.7) 10 years = 3.19 (1.3 – 8.1)

5y

at the beginning of the study, )

3y 10y 5y 3y 10y

1. Moller et al: JACI 2002;109:251-6 2. Niggemann et al, Allergy 2006; 61: 855-859 3.

Jacobson et al., Allergy 2007; 62:943-8

Coseasonal SLIT Reduces The Development Of Asthma In Children With ARC

Methods: Open study of 113 children aged 5 to 14 years with

grass-pollen AR were randomized to receive co-seasonal SLIT

for 3 years or standard symptomatic therapy. None with

asthma at baseline.

◦ Active treatment: Feb-June for 3 yrs, build-up 15 days,

◦ Maintenance dose: 0.5 mcg major grass allergen grp 5

given 5 days a week (11 mcg major grass CMD=low dose)

Novembre J Allergy Clin Immunol 2004;114:851-7.)

SLIT Reduces Risk of Developing Asthma

0%

20%

40%

60%

80%

100%

SLIT Control

% o

f p

ati

en

ts

w asthma

w/o asthma

Novembre E et al. J Allergy Clin Immunol 2004; 114: 851-7

Odds ratio 3.80 (1.5-10.0)

80% 60% n=8

n=37

20%

40%

n=18

n=26

Three years of coseasonal SLIT reduces the development of seasonal asthma in children with hay fever

Effects of SCIT with Parietaria on Symptoms and Progression to Asthma

Changes in symptom scores at the peak season for allergic rhinitis in adult patients

Rhinitis patients developing

asthmatic symptoms

Polosa et al. Allergy 2004;59:1224-8

200

0

2000

30 with SAR patients randomly assigned to SCIT or placebo for 3 year. Monthly maintenance 4.8 mcg of the major allergen Par j 1

Greater risk of incident asthma cases in adults with allergic rhinitis and effect of allergen

immunotherapy: a retrospective cohort study. .

• Objective: investigate history of allergic rhinitis as a risk factor for asthma and the potential effect of SIT

• Method: cohort of non-asthmatic adults ± AR, aged 18–40 yr in 1990-91, were retrospectively followed up until 2000.

– asthma diagnosis, history of SIT, second-hand smoking and the presence of pets in the household

• A total of 436 of the 1104 non-asthmatic adults were available for final analyses

Polasa et al. Respir Res. 2005 28;6:153

AIT Lowers the risk of the development of new asthma cases in adults with allergic rhinitis.

Highest odds ratio: associated with asthma development was AR (10.26)

Lowest odds ratio: SCIT treatment was significantly and inversely related to the development of new onset asthma (OR, 0.63)

Polasa Respir Res. 2005 28;6:153.

Des Roches A. et al. J Allergy Clin Immunol, 1997;99(4):450-453.

1/5

To determine whether SCIT can prevent the development of new sensitizations over a 3-years follow-up survey in children suffering from asthma due House Dust Mite

• 44 children (4 to 6 years) with asthma, monosensitized to HDM. - Clinical history of asthma clearly established, - Positive skin prick test response to D. pteronyssinus. and DM

sIgE SCIT treatment: 2 µg of Der p 1) every 2 weeks for 1 year, and then every month over the next 2 years.

SIT in children monosensitized to HDM alters the natural course of allergy in preventing the development of new sensitizations.

– New sensitizations was significantly less in monosensitized children who received SIT than in children in the control group (p < 0.001).

– Ten of 22 (45%) who received SIT did not develop new sensitivities

– Zero in the control group. did not develop new sensitivities

Des Roches A. et al. J Allergy Clin Immunol, 1997;99(4):450-453.

New sensitivities (number of patients)

Initial sensitivity

No. of patients

None Cat Dog Alt Grass

SIT group 22 10 6 4 2 1

Control group 22 0 12 8 6 6

Famed "Show Me the Money!" scene

AIT is it Cost-effectiveness?

“Although, the primary means for assessing outcome A/I clinical trials and practice has been clinical.., other outcomes, such as cost-effectiveness, will likely become increasingly more important to health care decision makers.

*Cox L, et al. Allergen immunotherapy practice in the United States: guidelines, measures, and outcomes. Ann

Allergy Asthma Immunol. 2011;107(4):289-99

Health Economics of SIT (15 Studies from 1995 to 2011)

82

YR/AUTHOR CT

SOURCE SUBJECTS ILLNESS COMPARATORS RESULTS

95 Buchner DE

Lit Rev Unspecified AR; Asthma SIT vs SDT AR $7,335/10 Years; Asthma $14,137/10 Years

‘97 Le Pen FR

Survey Unspecified Various 1-2 Years SIT vs <1 Year SIT

Not Provided

‘00 Schadlich DE

Clin Trial Unspecified AR 3 Years SIT vs SDT $960/10 Years Mite; $1,109/10 Years Pollen

‘05 Berto IT

MR Children AR ± Asthma Year Prior vs Year of SLIT $363/Year

‘05 Peterson DK

Survey 16-60 Years AR ± Asthma 4 Years SIT vs SDT $1,447/4 Years

‘06 Ariano IT

Diary Adults AR + Asthma 3 Years SIT v SDT; 3 Years FU

$932/Year in Year 6 (3rd Year FU)

‘06 Berto IT

RC 16-45 Years AR ± Asthma 3 Years SLIT+‘SDT vs SDT $632/6 Years (3rd Year FU)

‘07 Bachert Eur

Clin Trial Adults AR ± Asthma 3 Years SLIT+SDT vs SDT; 6 Years FU

$19,345 to $27,324 cost per QALY gained

‘07 Keiding UK

Clin Trial 18-60 Years AR 3 Years SLIT+SDT vs SDT; 6 Years FU

$14,536 to $38,695 cost per QALY gained

‘07 Omnes FR

Delphi Adults/ Children

AR ± Asthma 3 Years SIT Adults; 4 Years SIT Children; 3 Years FU

ICER (add’l improved pt): SCIT vs SDT $517 to $1,964; SLIT vs SDT $933 to $5,829

Poor outcomes for SIT are shown in red font.

Sustained significant reductions in cost beginning in the 3rd year subcutaneous allergen immunotherapy

• Results: In additional to reduced symptom/medication scores there was a significant difference in costs favor of SIT vs control – 15% the second year – 48% the third year (80% reduction ) – 80% reduction maintained up to 6th year, 3 years after stopping

immunotherapy

• Net saving per patient: $830/year.

• Conclusion: SCIT has significant economic advantages over pharmocotherapy alone

Ariano et al Allergy Asthma Proc 2006;27

• Results: Significant 18-month total health care cost reduction in AIT group compared with control

– 42% children

– 30% adults

• Significant savings seen beginning at 3 months

Hankin J Allergy Clin Immunol 2013;131:1084-91.

Study: Retrospective (1997-2009) Florida Medicaid claims analysis compared mean 18-month health care costs of patients with newly diagnosed AR who received de novo AIT more versus matched controls who did not receive AIT

Hankin et al, J Allergy Clin Immunol 2013;131:1084-91.

Reductions include: inpatient, outpatient and pharmacy costs

SLIT versus SCIT For Asthma • Are they both effective?

• Yes, several meta-analyses have demonstrated efficacy of both symptoms & medication and secondary outcomes

• If so, are they equally effective?

• Magnitude may be greater for SCIT

• What determines efficacy for each method?

• Quality of extract, duration , other exposures for both

• Dose for SCIT range 5-20mcg, but SLIT effect may vary with allergen extract formulation

• Are they safe and how does safety compare between the two methods?

• SLIT appears to be safer but anaphylaxis has been reported & risk factors for SLIT not clearly identified

SLIT AND SCIT for Asthma

•Can they both prevent the progression of allergic disease?

Yes, both in terms of asthma and new allergen sensitizations

Pharmacotherapy only treats the ‘tip of the allergy iceberg’ with Allergen immunotherapy is the only immune modifying treatment. Sustained benefits after discontinuation and possible prevention of allergic disease progression