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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. Discuss allergic rhinitis and its impact on the population

2. Outline the pathophysiology of an immune response to allergens

3. Review the current immunotherapies

4. 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

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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

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V. Therapies to Treat Allergic Rhinitis

Table 1: Overall Therapies and Costs

Medication Class1

Role in Therapy1

Monthly Cost10

Over-The-Counter

Antihistamines

Sneezing, itching, rhinorrhea, ocular

symptoms

$15 - $30

Decongestants (Systemic) Nasal congestion $10 - $20

Intranasal Corticosteroids Sneezing, itching, rhinorrhea, and nasal

congestion

$30 - $50

Mast cell stabilizers Sneezing, itching, and rhinorrhea $10 - $20

Intranasal Anticholinergics Rhinorrhea and itching $20 - $30

Leukotriene Receptor

Antagonists

Adjunctive therapy with antihistamines

and in children with asthma and

coexisting allergic rhinitis

$25

Immunotherapy Inadequate controlled with

pharmacotherapy and environmental

control measures

$100 - $300

VI. Allergen Immunotherapy

A. Definition11

i. Repeated administration of specific allergens to patients with IgE-

mediated 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

C. Testing13

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 T-

helper1), and/or apoptosis of effector memory Th2 cells

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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

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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 Brand Name Use

Timothy grass pollen sublingual

extract

GrastekTM

Treatment of allergy to timothy and

similar grasses.

Grass pollen sublingual extract

(sweet vernal, perennial, rye,

timothy, Kentucky blue)

OralairTM

Allergic rhinitis with or without

allergic conjunctivitis.

Short ragweed pollen sublingual

extract

RagwitekTM

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

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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

Systemic allergic

reactions

Rhinitis

Higher risk for

anaphylaxis

Oral pruritus

Throat irritation

Ear pruritus

Mouth Edema

Tongue Pruritus

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

Objective(s) Investigate the efficacy and safety of timothy grass Allergen

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

Criteria Five to 17 years of age with a clinical history of physician-diagnosed

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

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at screening

Exclusion

Criteria 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

Methods 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

Statistics

Analysis 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

Results 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

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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)

Author’s

Conclusions 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

Comments Strengths

Blinding

Inclusion Criteria

Intent-to-treat population

Weakness

Population size

Length of study

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

Objectives

Confirm the efficacy of a rapidly dissolving grass allergen tablet

(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

Criteria 18 to 65 years old

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

Criteria Significant asthma outside the grass pollen season

FEV1 lower than 70% of predicted value

Allergic rhinitis requiring medication caused by allergens other than

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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

Methods 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 follow-

up (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

Statistical

Analysis 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

Results 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

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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

Author’s

Conclusions 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

Comments Strengths

Double-blinded

Starting treatment16 weeks

prior to study

Strict randomization protocol

Weakness

Including a baseline observational

year would confirm matching for

symptom and rescue medication use

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

Objectives

To evaluate grass sublingual immunotherapy tablet (MK-7243) treatment in

subjects with allergic rhinitis with or without conjunctivitis (AR/C)

Study Design Multicenter, double-blinded, randomized, placebo-controlled, parallel-

group study

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Study Site(s) United States and Canada

Inclusion

Criteria 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

Exclusion

Criteria 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 self-

injectable epinephrine

History of chronic sinusitis during the previous 2 years

Severe atopic dermatitis

Methods 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

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the event of an acute, severe, local or systemic allergic reaction

Statistical

Analysis 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)

Results 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

Author’s

Conclusions 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 self-

limiting, 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 Instructions

First Generation

Oral Antihistamines

Chlorpheniramine

maleate

4 mg 1 tablet Q6H

Diphenhydramine

hydrochloride

12.5 - 50 mg 1 tablet Q4 - 6H

Second Generation

Oral Antihistamines

Loratidine 5 - 10 mg 1 tablet once daily

Desloratidine 5 mg 1 tablet once daily

Fexofenadine 60 - 180 mg 60 mg tab twice daily

Cetirizine 5 - 10 mg 1 tablet once daily

Levocetirizine 5 mg 1 tablet once daily

Ophthalmic

Antihistamine

Olopatadine

Hydrochloride

Solution

0.1 - 0.2 % 1 drop in affected eye(s)

once or twice daily

Azelastine

Hydrochloride

0.05% 1 drop into affected

eye(s) twice daily

Intranasal

Antihistamines

Azelastine

Hydrochloride

0.1 - 0.15% 1 – 2 sprays in each

nostril twice daily

Olopatadine 665 mcg 2 sprays each nostril

twice daily

Oral

Decongestants

Pseudoephedrine 60 -120 mg 60 mg tab Q4 - 6 hours

Phenylephrine 10 - 20 mg 10 mg Q4H as needed

Intranasal

Corticosteroids

Beclomethasone

diproprionate

42 - 84 mcg 1 - 2 sprays per nostril

once daily or twice daily

Budesonide 64 mcg 1 - 4 sprays per nostril

daily

Flunisolide 50 mcg 2 sprays per nostril twice

daily or three times daily

Fluticasone 100 mcg 2 sprays per nostril daily

Mometasone 100 mcg 2 sprays per nostril daily

Triamcinolone 110 mcg 1 - 2 sprays per nostril

daily

Ciclesonide 50 mcg 2 sprays in each nostril

once daily or 1 spray in

each nostril daily

Mast Cell

Stabilizers

Cromolyn Sodium 5.2 mg 1 – 2 sprays per nostril

four times daily

Intranasal

Anticholinergics

Ipratropium bromide 0.03 - 0.06% 2 sprays/nostril 2 – 4

times per day

Leukotriene

Receptor

Antagonist

Montelukast 4 - 10 mg 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)