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Active-ATE Your Immunity With GRASTEK
Regina N. Del Bosque, Pharm.D., R.Ph.
PGY1 Community Pharmacy Practice Resident
HEB Pharmacy/University of Texas at Austin College of Pharmacy
Resident Pharmacotherapy Rounds
October 31, 2014
Learning Objectives
1.
2.
3.
4.
Discuss allergic rhinitis and its impact on the population
Outline the pathophysiology of an immune response to allergens
Review the current immunotherapies
Explain the differences between Subcutaneous Immunotherapy (SCIT) and
Sublingual Immunotherapy (SLIT)
5. Outline current SLIT approved in the United States
6. Describe the controversy of SLIT
7. Evaluate the literature concerning the efficacy of SLIT in the treatment of grass
allergies
Del Bosque 1
I. Allergic Rhinitis and its Effects on the Population
A. Definition
i. Allergic rhinitis is an immunological disorder that develops in
individuals who have produced allergen-specific immunoglobulin
E (IgE) in response to environmental exposures1
B. Epidemiology
i. 17.6 million adults have been diagnosed with hay fever in 20122
ii. 6.6 million children have been diagnosed with hay fever in 20123
iii. 11.1 million visits to physicians offices with a primary diagnosis of
allergic rhinitis were made in 20124
iv. Accounts for 2 million lost school days per year and 6 million lost
work days
C. Medical Cost
i. Medical spending to treat allergic rhinitis almost doubled from
2000 to 2005 from 6.1 to 11.2 billion dollars5
II. Pathophysiology of an Immune Response to Allergens
A. Allergens interact with specific IgE molecules bound to nasal mast cells
and basophils1
B. Airborne allergens enter the nose and are processed by lymphocytes,
which produce antigen-specific IgE, thereby sensitizing genetically
predisposed hosts to those agents
C. Upon nasal reexposure, IgE bound to mast cells interacts with airborne
allergen, triggering release of inflammatory mediators in increased
quantities
D. Immediate reactions occurs within seconds to minutes resulting in the
rapid release of histamine, leukotrienes, prostaglandin D2, tryptase, and
kinins6
i. Sensory nerve stimulation produces itching
ii. Sneezing occurs via reflex stimulation of efferent vagal pathways
iii. Neuropeptides substance P and calcitonin gene-related peptide
from non-adrenergic, non-cholinergic nerves affect vascular
engorgement directly and via modulation of sympathetic tone
while histamine produces rhinorrhea, itching, and sneezing
iv. Inflammatory mediators also produce vasodilation, increased
vascular permeability, and production of increased nasal secretions
E. Late phase reaction occurs 4 to 8 after the initial exposure to an allergen
and occurs in 50% of allergic rhinitis patients1
i. Likely cause of the persistent, chronic symptoms of allergic rhinitis
including nasal congestion
ii. The process also causes significant increase in nonspecific
irritability
iii. Symptoms secondary to the late-phase reaction, predominantly
nasal congestion begin 3 to 5 hours after antigen exposure and
peak at 12 to 24 hours
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F. Clinical presentation of allergic rhinitis includes clear rhinorrhea,
paroxysms of sneezing, nasal congestion, postnasal drip, and pruritic eyes,
ears, nose, or palate
III.
Risk Factors for Allergic Rhinitis7
A. Genetic predisposition to develop allergic diseases
B. Birth during the pollen season
C. Firstborn status
D. Maternal smoking exposure in the first year of life
E. Serum IgE > 100 IU/mL before age six
IV. Treatment Algorithm for Allergic Rhinitis8,9
A. First identify Allergic Rhinitis
i. Allergen avoidance and patient education
1. Appropriate training and education for patients and families
is fundamental to the management of allergic disease
2. Identify the allergen and avoid exposure to triggers
a. Wash bed sheets in warm water weekly
b. Vacuum carpet weekly with high-efficiency
particulate air (HEPA) filtration system
c. Keep humidity levels less than 50% with a
dehumidifier
d. Avoid indoor house plants
ii. Mild Intermittent Symptoms
1. Treat with second generation oral or intranasal
antihistamine, as needed
iii. Mild to Moderate Symptoms
1. First line is treatment with intranasal corticosteroids
2. Can also consider nasal irritation or decongestants for nasal
congestion, ipratropium or intranasal antihistamines for
rhinorrhea, or oral antihistamines for nasal ocular
symptoms
iv. Severe Persistent Symptoms
1. Treat with intranasal corticosteroids plus oral or intranasal
antihistamine, oral leukotriene receptor antagonist, or
intranasal Cromolyn
a. If symptoms persist consider immunotherapy or
alternative treatments
Del Bosque 3
V. Therapies to Treat Allergic Rhinitis
Table 1: Overall Therapies and Costs
Medication Class1
Role in Therapy1
Over-The-Counter
Sneezing, itching, rhinorrhea, ocular
Antihistamines
symptoms
Decongestants (Systemic)
Nasal congestion
Intranasal Corticosteroids
Sneezing, itching, rhinorrhea, and nasal
congestion
Mast cell stabilizers
Sneezing, itching, and rhinorrhea
Intranasal Anticholinergics Rhinorrhea and itching
Leukotriene Receptor
Adjunctive therapy with antihistamines
Antagonists
and in children with asthma and
coexisting allergic rhinitis
Immunotherapy
Inadequate controlled with
pharmacotherapy and environmental
control measures
Monthly Cost10
$15 - $30
$10 - $20
$30 - $50
$10 - $20
$20 - $30
$25
$100 - $300
VI. Allergen Immunotherapy
A. Definition11
i. Repeated administration of specific allergens to patients with IgEmediated conditions for the purpose of providing protection against
the allergic symptoms and inflammatory reactions associated with
natural exposure to these allergens
B. Role of Therapy – Target Patient Population12
i. A patient is a candidate for allergen immunotherapy only if it has
been established that there is a clinically important allergic
component to their disease. Patients must have both of the
following:
1. Symptoms upon natural exposure to the allergen
2. The present of specific IgE to the allergen in question,
demonstrated either through allergen skin testing or serum
tests or allergen-specific IgE
13
C. Testing
i. Prick/puncture
1. Most appropriate diagnostic method in the absence of
contraindications
2. Application of droplets is a 1:10 or 1:20 weight/volume
allergen extract solutions
3. Standardized allergenic extracts used are labeled as
bioequivalent allergy units (BAU)
4. Test performed most often on the forearm, upper arm, or
back
5. Clean area with alcohol solution
6. A positive control and negative control are used to verify
the patient’s normal response
7. Allergen extract solution is pricked under the skin’s surface
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8. The health care provider closely watches the skin for
swelling and redness or other signs of a reaction
9. Results are usually seen within 15-20 minutes
10. Positive test equals a wheal that is equal to or larger than
the histamine control or > 3 millimeters (mm) in diameter
ii. Intradermal
1. Injecting a small amount of allergen into the skin
2. The health care provider watches for a reaction at the site
3. This test is more likely to be used to find out if you are
allergic to something specific (ex. bee venom or penicillin)
100 to 1000 fold more sensitive
4. False-positive reactions are more common
5. Injection of 0.02 to 0.05 ml of a 1:500 to 1:1000
weight/volume allergen extract into the skin
6. 26 or 27 gauge needle positioned at 45 degree angle is used
to make a 2 to 3 mm “bleb” of extract intradermally
7. Positive test if a wheal of 5 mm or larger in most cases
8. Intradermal tests are more reproducible than prick/puncture
skin tests and are more sensitive
D. Differences from allergy medications14
i. In contrast with symptomatic treatment with anti-allergic drugs,
immunotherapy is the only available therapy that treats the
underlying cause of the disease, with proven long-term benefits.
VII. Background Information about Immunotherapy Therapy
A. Subcutaneous Immunotherapy
i. The use of SCIT began in 1911 by Leonard Noon and John
Freeman15
ii. More than 30 million injections are administered annually14
iii. SCIT currently represents the standard immunotherapy15
B. Sublingual Immunotherapy
i. In the 1990’s SLIT first appeared on the market outside of the
United States because physicians were requesting single specific
allergens for immunotherapy
ii. SLIT was first accepted as a viable alternative to SCIT in the
World Health Organization (WHO) position paper, published in
1998 and then include in the Allergic Rhinitis and Its Impact on
Asthma (ARIA) guidelines ARIA15
VIII. Mechanism of Action of Allergen Immunotherapy
A. Subcutaneous Immunotherapy (SCIT)15,16
i. Suppresses allergic T-helper 2 (Th2) -mediated inflammation and
increases antigen-specific Immunoglobulin G (IgE), by induction
of regulatory T cells (Tregs), immune deviation (Th2 to Thelper1), and/or apoptosis of effector memory Th2 cells
Del Bosque 5
ii. Increases in allergen-specific IgE, thereby blunting of seasonal
increases in IgE, and increases in allergen-specific IgG,
particularly IgG4 and IgA
B. Sublingual Immunotherapy (SLIT)15,16
i. The proposed mechanism is similar to SCIT but also includes the
oral mucosa which is a site of natural immune tolerance
ii. Oral mucosa includes the presence of Langerhans cells, epithelial
cells and monocytes capable of producing IL-10, TFG-Beta, and
activins may play a role in the maintenance of oral tolerance
IX. Subcutaneous Immunotherapy Administration
A. Administration is through a 26 to 27- gauge syringe with a 1/2 or 3/8 inch
non-removable needle
i. Injection should be given subcutaneously in the posterior portion
of the middle third of the arm at the junction of the deltoid and
tricep muscles8
B. Two phases of allergen immunotherapy administration8
i. Build-up Phase
1. Dose and concentration of allergen immunotherapy extract
are increased
2. Consist of three or four 10-fold dilutions of the
maintenance concentrate
3. Volume is increased depending on the patients sensitivity
to the extract, the history of prior reactions, and the
concentration being delivered
4. Administration can be 1 to 3 times per week
5. Reach maintenance dose in 3 to 6 months depending on
starting dilution
ii. Maintenance Phase
1. Considered an effective therapeutic dose over a period of
time
2. Intervals of 2 to 4 weeks between injections is
recommended
3. Patients should be evaluated at least every 6 to 12 months
while receiving immunotherapy
4. Duration of therapy individualized based on the patient’s
clinical response, disease severity, immunotherapy reaction
history, and preference
5. A decision about continuation of effective immunotherapy
should generally be made after the initial period of 3 to 5
years of treatment
Del Bosque 6
X. Sublingual Immunotherapy Administration
A. Administration17
i. First dose under supervision of a physician with experience in the
diagnosis and treatment of allergic diseases and observed for at
least 30 minutes following initial dose
ii. Allergen is formulated into a rapidly dissolving tablet that is held
under the tongue until completely dissolved. Do not swallow for at
least 1 minute
iii. Tablets thereafter are self administered once daily
XI. Sublingual Immunotherapy Therapy Approved in the United States18
Table 2: Sublingual Immunotherapy
Generic Name
Timothy grass pollen sublingual
extract
Grass pollen sublingual extract
(sweet vernal, perennial, rye,
timothy, Kentucky blue)
Short ragweed pollen sublingual
extract
Brand Name
GrastekTM
OralairTM
RagwitekTM
Use
Treatment of allergy to timothy and
similar grasses.
Allergic rhinitis with or without
allergic conjunctivitis.
Treatment of allergy to ragweed
A. Sublingual Immunotherapy Options
i. GrastekTM
1. Therapy begins 12 weeks before the expected onset of the
allergy-inducing pollen season
2. Initiated at the maintenance dose (2800 BAU
[bioequivalent allergy unit] Amb a 1 unit)
3. Cost: $8.30/tablet or $249/month
ii. OralairTM
1. Therapy begins 16 weeks before the expected onset of the
allergy-inducing pollen season
2. Dose titration is required in patients 10 – 17 years of age
and completed over 3 days at home. In patients 18 to 65,
no dose titration is needed; treatment is initiated at the
maintenance dose of 300 Index of Reactivity (IR)
a. Day 1: 100 IR
b. Day 2: 2 x 100 IR
c. Day 3 and following: 300 IR
3. Cost: $10/tablet or $300/month
iii. RagwitekTM
1. Therapy begins 12 weeks before the expected onset of the
allergy-inducing pollen season
2. Initiated at the maintenance dose (2800 BAU
[bioequivalent allergy unit] Amb a 1 unit)
3. Cost: $8.30/tablet or $249/month
Del Bosque 7
XII. Differences between Subcutaneous Immunotherapy and Sublingual Immunotherapy
Table 3: Differences between Subcutaneous Immunotherapy and Sublingual
Immunotherapy
Differences
SCIT
SLIT
Location of Administration Doctors Office
Patients Home
Site of Administration
Injection
Sublingual
Systemic Effects
 Local site irritation
 Oral pruritus
 Systemic allergic
 Throat irritation
reactions
 Ear pruritus
 Rhinitis
 Mouth Edema
 Higher risk for
 Tongue Pruritus
anaphylaxis
 Oral paresthesia
Costs
~ $1,000/year
~$3,000/year
XIII. Criteria for approval of Immunotherapy by Food Drug Administration (FDA)
A. In order for an allergen immunotherapy therapeutic agent to get approved by the
US Food and Drug Administration (FDA), two statistical efficacy criteria must be
met:
a. The Total Combined Score (TCS) must demonstrate an average relative
difference of 15 percent compared with placebo, and
b. The upper bound of the 95% confidence interval must be ≤ -10 percent
XIV. Sublingual vs. Subcutaneous Immunological Therapy: Literature Review
Blaiss M, Maloney J, Nolte H, et al. Efficacy and safety of timothy grass allergy
immunotherapy tablets in North American children and adolescents. J Allergy Clin
Immunol 2011; 127:64.19
Investigate the efficacy and safety of timothy grass Allergen
Objective(s)
Immunotherapy in North American children/adolescents ages 5 years of age
and older with grass pollen-induced allergic rhinoconjunctivitis (ARC) with
or without asthma
Study Site(s)  41 sites in the United States and 8 Canadian sites
Study Design  Double-blind, randomized, placebo-controlled, parallel-group,
multicenter, phase 3 study conducted between April 2008 and
September 2009
 Observation period and treatment period
Inclusion
 Five to 17 years of age with a clinical history of physician-diagnosed
Criteria
grass pollen-induced ARC with or without asthma
 Moderate-to-severe ARC; treatment was during previous General Pollen
Season (GPS)
 Positive skin prick test response to P pratense (standardized timothy
grass extract) with average of horizontal and vertical wheal diameters 5
mm or larger than elicited by saline control
 Positive specific IgE level against P pratense of 0.7 kU/L or greater
 Forced Expiratory Volume1 (FEV1) of 70% or greater of predicted value
Del Bosque 8
at screening
Exclusion
Criteria
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Methods
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Statistics
Analysis
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Results
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Clinical history of symptomatic seasonal or perennial ARC, asthma, or
both requiring medication because of an allergen other than grass during
or potentially over-lapping the GPS
Immunosuppressive treatment in the 3 months before screening
Clinical history of persistent severe asthma, chronic
urticarial/angioedema or chronic rhinosinusitis or current severe atopic
dermatitis
For subjects who participated in the observation period and did not
experience a rhinoconjunctivitis score increase of 4 points or more for at
least 2 days compared with the preseason score or did not use ARC
symptomatic medication for at least 2 days during the observational
period were also excluded
Subjects were randomized 1:1 to a once-daily sublingual dose of 2,800
bioequivalent allergen units of grass Allergen Immunotherapy Tablet
(AIT) treatment or placebo
Subjects and investigators were blinded to treatment
Treatment began approximately 16 weeks before the GPS and continued
through the entire GPS for a total treatment period of 23 weeks
First 3 daily doses of study medication were administered at the study
site, and the subjects were monitored for adverse events (AEs) on site
for 30 minutes after administration, subsequent doses were taken at
home
Primary end point of the study was total combined score (TCS), sum of
rhinoconjunctivitis daily symptom score (DSS) and the daily medication
score (DMS) averaged over the entire GPS
Secondary endpoints were average DSS and average DMS over the
entire GPS and the combined average weekly score from the validated
Juniper Pediatric Rhinoconjunctivitis Quality of Life Questionnaire
(RQLQ for ages 6 - <11 years (5 year olds did not complete the
questionnaire
Subjects/parents/guardians scored daily rhinoconjunctivitis symptoms
Safety was measured based on spontaneously reported AEs
Power analysis revealed 340 subjects would be sufficient to detect a 5%
level of significance (2-sided test)
Primary end points were evaluated by using a linear model with asthma
status, study site, and treatment group as fixed effects and adjusting for
different error variation for each treatment group
Intent-to-treat population
345 children were randomized, 344 received at least 1 dose of study
treatment, and 282 completed the study
Intent-to-treat population consisted of 149 subjects in the grass AIT
group and 158 subjects in the placebo group
Significant improvement in the grass AIT group relative to placebo of
Del Bosque 9
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Author’s
Conclusions
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Comments
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81% (P = 0.006) Appendix 2: Table 5
Improvements in the mean TCS, DSS, and DMS in the GPS for grass
AIT treatment relative to placebo were 31% (P < 0.001), 28%
(P <0.001), and 41% (P = 0.05)
Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score for the
grass AIT group compared to placebo was a difference of 0.72 and 38%
improvement (P = 0.005) Appendix 2: Table 5
No significant reduction in asthma DSS
75% experienced treatment-related AEs (oral pruritus and throat
irritation were most common) Appendix 2: Table 6
Serious AEs were reported by 5 subjects (none treatment related)
First study to demonstrate the efficacy and safety of timothy grass AIT
treatment in a predominantly multi-sensitized North American pediatric
population
The results from this trial confirm that grass AIT treatment can
effectively improve ARC symptoms, decrease the need for allergy
rescue medication, and improve rhinoconjunctivitis quality of life in
children/adolescents 5 years of age and older with ARC to timothy grass
and other related grasses
Strengths
Weakness
Blinding
 Population size
Inclusion Criteria
 Length of study
Intent-to-treat population
 Inability to detect a treatment
effect for asthma
Dahl R, Kapp A, Colombo G, et al. Efficacy and safety of sublingual immunotherapy
with grass allergen tablets for seasonal allergic rhinoconjunctivitis. J Allergy Clin
Immunol 2006; 118:434.20
Confirm the efficacy of a rapidly dissolving grass allergen tablet
Objectives
(GRAZAX) compared with placebo in patients with seasonal
rhinoconjunctivitis
Study Site(s)  51 centers in 8 countries (Austria, Denmark, Germany, Italy, The
Netherlands, Spain, Sweden, and United Kingdom)
Study Design  Randomized, parallel-groups, double-blinded, and placebo-controlled
Inclusion
 18 to 65 years old
Criteria
 At least 2-year clinical history of significant grass-pollen induced
allergic rhinoconjunctivitis
 Specific IgE against Phleum pretense CAP class  2
 Positive skin prick test against Phleum pretense
 Wheal diameter  3 millimeters
 FEV1 higher than 70% of predicted value
Exclusion
 Significant asthma outside the grass pollen season
Criteria
 FEV1 lower than 70% of predicted value
 Allergic rhinitis requiring medication caused by allergens other than
Del Bosque 10
Methods
Statistical
Analysis
Results
grass during the treatment period
 Conjunctivitis, rhinitis, or asthma at the screening or randomization
visits
 History of anaphylaxis
 Immunosuppressive treatment
 Receipt of immunotherapy with grass pollen allergen within the
previous 10 years or any other allergen within the previous 5 years
 Pregnancy
 634 patients were randomized 1:1 receiving either an orodispersible
grass allergen tablet 75,000 SQ-T (GRAZAX) approximately 15
micrograms major allergen Phleum or a placebo tablet similar in taste,
smell, and appearance once daily
 Treatment started 16 weeks before the expected start of the grass pollen
season and continued for another 2 years, followed by 2 years of followup (results are from the first treatment season)
 Patients would rate symptoms of rhinoconjunctivitis on a scale from 0 to
3 and based on symptoms had free access to relief medication
(desloratidine, budesonide nasal spray, and oral prednisone)
o Final medication and symptom scores were calculated as the mean
of the total daily scores recorded throughout the whole 2005 pollen
season
 Determination of improvement of rhinoconjunctivitis symptoms by
asking questions of improvement from previous grass pollen seasons
 All other data were collected at 7 visits in the clinic and subjects were
reporting data for the efficacy of analysis into an electronic diary on a
daily basis
 Primary efficacy end point was the average rhinoconjunctivitis
symptom score during the grass pollen season
o Data of average rhinoconjunctivitis symptom score in the grass
pollen season necessary for the calculations were estimated form the
previous dose-ranging study (reference article 14)
o Reduction of at least 25% in symptom score can be discovered with
a 5% significance level and a power of 95% with a sample size of
268 patients in each arm
 634 subjects were randomized, 546 subjects completed the first
treatment year
o 88 subjects withdrew and of these 24 withdrew because of adverse
events
 Study population was 372 male subjects and 262 female subjects
 281 subjects had moderate and 353 subjects had severe grass pollen
allergy
 Average history of grass pollen allergy was 16 years
 Average age was 34.2 years old
 Length of preseasonal treatment ranged from 16 to 35 weeks
Efficacy
Del Bosque 11

Author’s
Conclusions
Comments
The reduction over placebo was 30% in symptom score and 38% in
medication score over the entire grass pollen season (P<0.001)
 Significant reductions over placebo were present from the start of the
grass pollen season (P<0.001). Appendix 3: Figure 1
 Subjects treated with the grass allergen tablet on average had 27 (53%)
well days during the grass pollen season versus 23 (44%) well days for
placebo (P <0.0001)
 Visual analog scale (VAS) score was 31% in the grass pollen season
(P<0.0001) by subjects treated with the grass allergy tablet
 Rhinoconjunctivitis symptoms compared to previous GPS demonstrated
that 82% of patients who received active treatment responded, compared
with 55% on placebo, an overall improvement in response rate of 49%
(P<0.0001)
Safety
 265 (84%) subjects treated with grass allergen tablets and 205 (64%)
treated with placebo reported at least 1 adverse event (AE) Appendix 3:
Table 8
o Half of the reported events were assess unlikely to the study drug
 24 of 634 patients withdrew due to AEs were resolved with reliever
medication or simple painkiller and there was no use of adrenaline
o 5 cases were treatment-related and initiated by the investigator
 Comparison of efficacy between the grass allergen tablet and placebo
showed highly statistically significant improvements in favor of the
active treatment for all endpoints tested
 Grass allergen tablet resulted in 30% decrease in rhinoconjunctivitis
symptoms in the face of an additional 38% reduction in the use of
reliever medication
 Both null hypothesis were clearly rejected at the 5% test level
(P<0.0001) improvement for rhinoconjunctivitis symptom score and
rhinoconjunctivitis medication was confirmed
Strengths
Weakness
 Double-blinded
 Including a baseline observational
year would confirm matching for
 Starting treatment16 weeks
symptom and rescue medication use
prior to study
 Strict randomization protocol
Maloney J, Bernstein DI, Nelson H, et al. Efficacy and safety of grass sublingual
immunotherapy tablet, MK-7243: a large randomized controlled trial. Ann Allergy
Asthma Immunol 2014; 112: 146.21
To evaluate grass sublingual immunotherapy tablet (MK-7243) treatment in
Objectives
subjects with allergic rhinitis with or without conjunctivitis (AR/C)
Study Design  Multicenter, double-blinded, randomized, placebo-controlled, parallelgroup study
Del Bosque 12
Study Site(s)
Inclusion
Criteria
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Exclusion
Criteria
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Methods
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United States and Canada
5-65 years old, of either sex and any race
Physician diagnosed history of grass pollen-induced AR/C with or
without asthma who had received treatment for their AR/C during the
previous GPS
Positive skin prick test response to P pratense (5-mm wheal compared
with saline control, 100,00 BAU/mL; ALK-Abello, Round Rock,
Texas); positive specific IgE against P pratense (IgE class 2; 0.7
kU/L)
FEV1 70% of the predicted value at screening and randomization visits
Subjects were required to have an electrocardiogram reading at
screening within normal limits or clinically acceptable
Adhere to dose and visit schedules
Female subjects of child-bearing potential were required to provide a
negative pregnancy test result at screening and remain abstinent or use 2
acceptable methods of birth control during treatment
Clinical history of symptomatic AR/C and/or asthma requiring regular
medications for another seasonal allergen during or potentially
overlapping with the GPS or for a perennial allergen to which the
subject was regularly exposed
Immunosuppressive treatment within the past 3 months (except steroids
for allergic/asthma symptoms)
History of severe asthma
Previous immunotherapy with any grass pollen allergen for longer than
1 month within the last 5 years
Pregnant, breast-feeding, or intended to become pregnant
Receiving ongoing specific immunotherapy at screening
Intolerance to ingredients of the study drug, rescue medications, or selfinjectable epinephrine
History of chronic sinusitis during the previous 2 years
Severe atopic dermatitis
A total of 1,501 subjects who continued to qualify for the study were
randomized in a 1:1 ratio according asthmatic status and age category
(5 - <18 or 18 -  65 years)
The tablets were supplied as fast-dissolving neutral tasting oral
lyophilisates for sublingual administration
Subjects were treated with once daily with placebo or MK-7243 for at
least 12 weeks before and during the entire 2012 GPS
Washout period (30 days) for inhaled corticosteroids before the
preseasonal visit (approximately 2 weeks before the start of GPS)
During GPS all subjects had access rescue medications
First dose of MK-7243 or placebo was administered at the study site,
with subjects monitored for 30 minutes after dosing for AEs.
Subsequent doses were administered at home
Each subject was supplied with self-injectable epinephrine to be used in
Del Bosque 13
Statistical
Analysis
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Results
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Author’s
Conclusions
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the event of an acute, severe, local or systemic allergic reaction
Primary end point was the total combined score (TCS), the sum of the
daily symptom score (DSS) and daily medication scores (DMS)
averaged over the GPS
Key secondary end points were the average DDS over the GPS, the
average TCS during the peak GPS, the average rhinoconjunctivitis
quality-of-life questionnaire with standardized activities for subjects 
12 years of age score during the peak GPS, and the average DMS over
the GPS
Intent-to-treat principle was applied including all subjects who had
received at least 1 dose of study medication and provided at least 1
efficacy measurement during the corresponding evaluation period
Safety analysis was based on all subjects as treated ( 1 dose of study
medication)
1,501 subjects were randomized, including 283 younger than 18 years;
1,498 subjects received 1 dose of study medication
1,255 (84%) randomized subjects completed the treatment period
1,301 subjects who received at least 1 dose of the study medication and
provided at lest 1 TCS measurement during the GPS were included in
the primary efficacy analysis
MK-7243 yielded a reduction vs. placebo of 23% (P<0.001) in median
TCS over the entire GPS and 29% reduction in median TCS over the
peak GPS Appendix 4: Figure 2
MK-7243 yield a 20% (P = 0.001) reduction vs. placebo in median DSS
over the entire GPS and a 20% reduction in DSS vs. placebo during the
peak GPS Appendix 4: Table 10
MK-7243 yield reductions vs. placebo of 23% (P<0.001) and 24%
(P=0.02) in median total nasal symptom score and total ocular symptom
score
MK-7243 was generally well tolerated up to 34 weeks of treatment; the
majority (>90%) of AE were assessed as mild or moderate in severity
Seven percent of all AEs were assessed as severe
Adverse events were primarily local application-site reactions and no
safety signal in subjects with asthma was apparent
MK-7243 is associated with significant decreased in TCS and its
components, DMS and DSS, versus placebo
MK-7243 treatment with oral antihistamines alone, such as loratidine
allowed in the present study, has been shown to reduce grass pollen
AR/C symptoms by only 8% compared with placebo
Safety result observed in this study showed that most AEs were selflimiting, mild or moderate local application-site reactions
o Showing sufficiency to permit at home administration
Showed that the same 2,800-bioequivalent allergy units (BAU)
MK-7243 dosage was well tolerated without up-titration by subjects in
the adult and pediatric subgroups
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Comments

Strengths
Timothy grass only was
observed to be effective
despite the fact that virtually
all subjects were sensitized
to cross-reactive northern
pasture grasses


Weakness
Weak pollen count observed in this
study was 23 grains/m3
Funded by Merck and Co, Inc.
XV. Conclusions
A. Evaluate the patient when considering SCIT or SLIT
i. Therapy that has been failed in the past
ii. Patient convenience and fears of SCIT
iii. Cost of therapy
B. Identify if the grass pollen season in the area of the patient is appropriate
for the corresponding SLIT
References
1. Joseph T. DiPiro, Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G.
Wells, L. Michael Posey. Pharmacotherapy: A Pathophysiologic Approach, 9th
Edition. Chapter 76. Allergic Rhinitis.
2. Blackwell, Debra L, Lucas, Jacqueline W, Clarke, Tainya C. Summary Health
Statistics for U.S. Adults: National Health Interview Survey, 2012, table 3 and 4.
U.S. Department of Health and Human Services. February 2014.
3. Blackwell, Debra L, Lucas, Jacqueline W, Clarke, Tainya C. Summary Health
Statistics for U.S. Children: National Health Interview Survey, 2012, table 2. U.S.
Department of Health and Human Services. February 2014.
4. National Ambulatory Medical Care Survey: 2010 Summary Tables, table 13.
Centers for Disease Control and Prevention – National Center for Health
Statistics.
5. Soni A. Allergic rhinitis: trends in use and expenditures, 2000 to 2005. Statistical
Brief #204, Agency for Healthcare Research and Quality; Bethesda, MD 2008.
6. Wilson SJ, Shute JK, Holgate ST, et al. Localization of interleukin (IL)-4 but not
to human mast cell secretory granules by immunoelectron microscopy. Clin Exp
Allergy 2000;30:493–500.
7. Gendo K, Larson EB. Evidence-based diagnostic strategies for evaluating
suspected allergic rhinitis. Ann Intern Med. 2004;140(4):278.
8. Cox L, Nelson, H, Lockey, R. Allergen immunotherapy; A practice parameter
third update. Task force report.
9. Sur, Denise K, Scandale, Stephanie. David Geffen School of Medicine,
University of California, Los Angeles, California. American Family
Physician. 2010 Jun 15;81(12):1440-1446.
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10. Deguzman, David A, Bettcher, Catherine, Harrison, R V, et al. Allergic Rhinitis.
Faculty Group Practice Quality Management Program. University of Michigan.
Blue Cross Blue Shield Maximum Allowable Cost. OTC products:
www.drugstore.com/
11. Cox L, Li J, Lockey R, Nelson H. Allergen immunotherapy: a practice parameter
second update. J Allergy Clin Immunol 2007;120(suppl):S25-85, IV.
12. deShazo, Richard. Kemp, Stephen, Corren, Jonathan, et al. Overview of
immunologic treatments for allergic rhinitis. UpToDate.
13. Bernstein IL, Li JT, Bernstein DI, Hamilton R, et al. American Academy of
Allergy, Asthma and Immunology; American College of Allergy, Asthma and
Immunology. Allergy diagnostic testing: an updated practice parameter. Ann
Allergy Asthma Immunol. 2008 Mar;100(3 Suppl 3):S1-148.
14. The Asthma Center. Immunotherapy. Education and Research Fund Advisor.
theasthmacenter.org.
15. Nouri-Aria KT, Wachholz PA, Francis JN, Jacobson MR, Walker SM, Wilcock
LK, et al. Grass pollen immunotherapy induces mucosal and peripheral IL-10
responses and blocking IgG activity. J Immunol. 2004;172:3252–3259.
16. Mubeccel, Akdis, Cezmi et al. Journal of Allergy and Clinical Immunology.
Mechanisms of allergen-specific immunotherapy.. April 2007/ Volume 119, Issue
4, Pages 780-789.
17. GrastekTM [package insert]. Whitehouse, NJ: Merck & Co., Inc; 2014.
18. American Academy of Allergy Asthma and Immunology. Allergy and Asthma
Medication Guide: Sublingual Immunotherapy. June 2014.
19. Blaiss M, Maloney J, Nolte H, et al. Efficacy and safety of timothy grass allergy
immunotherapy tablets in North American children and adolescents. J Allergy
Clin Immunol 2011; 127:64.
20. Dahl R, Kapp A, Colombo G, et al. Efficacy and safety of sublingual
immunotherapy with grass allergen tablets for seasonal allergic
rhinoconjunctivitis. J Allergy Clin Immunol 2006; 118:434.
21. Maloney J, Bernstein DI, Nelson H, et al. Efficacy and safety of grass sublingual
immunotherapy tablet, MK-7243: a large randomized controlled trial. Ann
Allergy Asthma Immunol 2014; 112: 146.
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Appendix 1:
Table 4: Overview of medications used for allergic rhinitis
Medication Class
Generic
Strengths
First Generation
Chlorpheniramine
4 mg
Oral Antihistamines maleate
Diphenhydramine
12.5 - 50 mg
hydrochloride
Second Generation Loratidine
5 - 10 mg
Oral Antihistamines Desloratidine
5 mg
Fexofenadine
60 - 180 mg
Cetirizine
5 - 10 mg
Levocetirizine
5 mg
Ophthalmic
Olopatadine
0.1 - 0.2 %
Antihistamine
Hydrochloride
Solution
Azelastine
0.05%
Hydrochloride
Intranasal
Azelastine
0.1 - 0.15%
Antihistamines
Hydrochloride
Olopatadine
665 mcg
Oral
Decongestants
Intranasal
Corticosteroids
Mast Cell
Stabilizers
Intranasal
Anticholinergics
Leukotriene
Receptor
Antagonist
Pseudoephedrine
Phenylephrine
Beclomethasone
diproprionate
Budesonide
60 -120 mg
10 - 20 mg
42 - 84 mcg
Flunisolide
50 mcg
Fluticasone
Mometasone
Triamcinolone
100 mcg
100 mcg
110 mcg
Ciclesonide
50 mcg
Cromolyn Sodium
5.2 mg
Ipratropium bromide
0.03 - 0.06%
Montelukast
4 - 10 mg
64 mcg
Instructions
1 tablet Q6H
1 tablet Q4 - 6H
1 tablet once daily
1 tablet once daily
60 mg tab twice daily
1 tablet once daily
1 tablet once daily
1 drop in affected eye(s)
once or twice daily
1 drop into affected
eye(s) twice daily
1 – 2 sprays in each
nostril twice daily
2 sprays each nostril
twice daily
60 mg tab Q4 - 6 hours
10 mg Q4H as needed
1 - 2 sprays per nostril
once daily or twice daily
1 - 4 sprays per nostril
daily
2 sprays per nostril twice
daily or three times daily
2 sprays per nostril daily
2 sprays per nostril daily
1 - 2 sprays per nostril
daily
2 sprays in each nostril
once daily or 1 spray in
each nostril daily
1 – 2 sprays per nostril
four times daily
2 sprays/nostril 2 – 4
times per day
1 tablet once daily
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Appendix 2:
Blaiss M, Maloney J, Nolte H, et al. Efficacy and safety of timothy grass allergy
immunotherapy tablets in North American children and adolescents. J Allergy Clin
Immunol 2011; 127:6419.
Table 5: TCS, DSSs, DMSs, and RQLQ scores* during the entire GPS and peak GPS
Table 6: Adverse Events Experience by  5%
of Subjects
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Appendix 3:
Dahl R, Kapp A, Colombo G, et al. Efficacy and safety of sublingual immunotherapy
with grass allergen tablets for seasonal allergic rhinoconjunctivitis. J Allergy Clin
Immunol 2006; 118:43420.
Table 8: Summary of treatment emergent
adverse events
Figure 1: Average daily scores and medication
usage during the grass pollen season
Table 9: Treatment-emergent adverse events
reported by  5% of subjects
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Appendix 4:
Maloney J, Bernstein DI, Nelson H, et al. Efficacy and safety of grass sublingual
immunotherapy tablet, MK-7243: a large randomized controlled trial. Ann Allergy
Asthma Immunol 2014; 112: 14621.
Figure 2: Mean daily total combined score and pollen count. Pollen season was defined
as starting on the first day of 3 consecutive days with a grass pollen count !10 grains/ m3
of air and ending on the last day of the last occurrence of 3 consecutive days with a grass
pollen count !10 grains/m3 of air.
Table 10: Most commonly reported Treatment Related Adverse Events (TRAE)
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