Current Status of Sublingual Immunotherapy in the U.S.Michael S. Blaiss, MDClinical Professor of Pediatrics and MedicineUniversity of Tennessee Health Science Center Memphis, Tennessee

Conflicts of InterestSpeakers Bureau: AstraZeneca, Merck, GSK, Sunovion, Takeda, Allergan, Nestles, Genentech, Meda, Bausch and LombConsultant: Sanofi, Merck, Sunovion, Allergan, Proctor & Gamble, Takeda, Allergan, JDP Therapeutics, Pfizer, Vectura

Learning ObjectivesCite the reasons for the difficulty to get approval of SLIT in the US.Understand the US data on the different methods of SLIT in front of the FDABe familiar with possible issues for SLIT use and be able to clearly recognize potential side effects

IntroductionThough SLIT is commonly used in many parts of the world but presently are no approved FDA SLIT materialsNumerous studies have been performed all over the world but only a small number were DBPCRemote practice of allergy commonly using SLITAugust 2011-BC Allergists doing SLIT-11.4%*This review will focus on US trials with SLIT*Sikora JM, Tankersley MS. Perception and practice of sublingual immunotherapy among practicing allergists in the United States: a follow-up survey. Ann Allergy. 2013.

The Allergies, Immunotherapy & RhinoconjunctivitiS (AIRS) Patient and Provider Surveys Leonard Bielory, MD Michael Blaiss, MDTimothy Craig, MDMark Dykewicz, MD James Hadley, MD Bryan Leatherman, MDJodi Luchs, MDGabriel Ortiz, PA-CDavid Skoner, MD Nicole Walstein, PA-C

Underwritten by Merck

*Overall Survey Design

PopulationSampling FrameInterview LengthCompleted SamplePatient Survey: 2/28/2012-5/2/2012 Diagnosed with hay fever, allergic rhinitis, rhino-conjunctivitis, nasal or eye allergies, and symptoms or medication for condition in past 12 months.Current Allergic Rhinoconjunctivitis: Aged 5+National LL + Cell RDD 34,030 HH Screened24.5 minutes2,765Health Care Provider Survey: 2/2/2012 4/2/2012 Direct patient care in an outpatient setting and see patients with allergies at least weekly.AllergistFamily MedicineOtolaryngology/ENTOphthalmologist/OptometristPediatricianNurse PractitionersPhysician AssistantsTOTALAMA/AOA Master ListAMA/AOA Master ListAMA/AOA Master ListOptometrist National ListAMA/AOA Master ListNP National ListPA National List

17.9 minutes100 75100 50 75 50 50500

Why Recommend IT?QIT4/11Why do you recommend immunotherapy for your patients? Multiple response. Base: providers who see 1+ patient with allergic rhinoconjunctivitis per week and recommend immunotherapy, 18+ N=398;

Recommend Subcutaneous orSublingual Immunotherapy to Children*QIT10a: Do you usually recommend subcutaneous or sublingual immunotherapy? Base: providers who see at least one patient

Specialty Distribution by Type of Immunotherapy ProvidedSubcutaneous N=199; Sublingual N=62. These Ns represent those providers who provide IT (IT17a) and who did not indicate that they had no patients on subcutaneous (IT18a) or sublingual (IT19a) IT. Ns by specialty are shown in parentheses with subcutaneous first.*

Chart1

0.0854271357

0.2713567839

0.0904522613

0.0904522613

0.0050251256

0.4572864322

Subcutaneous

Pediatrics, 9%

NP/PA, 9%

Ophthalmology/ Optometry, 1%

Allergy/ Immunology, 46%

Sheet1

Column1SubcutaneousSublingual

Family Medicine9%11%

Oto/ENT27%53%

Pediatrics9%3%

NP/PA9%16%

Ophthalmology/Optometry1%2%

Allergy/Immunology46%15%

To resize chart data range, drag lower right corner of range.

Specialty * Provide Shots and Have Patients Crosstabulation

Count

Provide Shots and Have PatientsTotalProvide Drops and have patients onTotal

1.001.00

SpecialtyFamily Medicine1717SpecialtyFamily Medicine7775Family Medicine9%11%

Otolaryngology/ENT5454Otolaryngology/ENT3333100Otolaryngology/ENT27%53%

Pediatrics1818Pediatrics2275Pediatrics9%3%

NP/PA1818NP/PA1010100NP/PA9%16%

Ophthalmology/Optometry11Ophthalmology/Optometry1150Ophthalmology/Optometry1%2%

Allergy/Immunology9191Allergy/Immunology99100Allergy/Immunology46%15%

Total199199Total6262

Specialty * Provide Drops and have patients on Crosstabulation

Count

Provide Drops and have patients onTotal

1.00

SpecialtyFamily Medicine77

Otolaryngology/ENT3333

Pediatrics22

NP/PA1010

Ophthalmology/Optometry11

Allergy/Immunology99

Total6262

Chart1

0.1129032258

0.5322580645

0.0322580645

0.1612903226

0.0161290323

0.1451612903

Sublingual

Ophthalmology/ Optometry, 2%

Allergy/ Immunology, 15%

Sheet1

Column1Sublingual

Family Medicine11%

Oto/ENT53%

Pediatrics3%

NP/PA16%

Ophthalmology/Optometry2%

Allergy/Immunology15%

To resize chart data range, drag lower right corner of range.

Specialty * Provide Shots and Have Patients Crosstabulation

Count

Provide Shots and Have PatientsTotalProvide Drops and have patients onTotal

1.001.00

SpecialtyFamily Medicine1717SpecialtyFamily Medicine7775Family Medicine9%11%

Otolaryngology/ENT5454Otolaryngology/ENT3333100Otolaryngology/ENT27%53%

Pediatrics1818Pediatrics2275Pediatrics9%3%

NP/PA1818NP/PA1010100NP/PA9%16%

Ophthalmology/Optometry11Ophthalmology/Optometry1150Ophthalmology/Optometry1%2%

Allergy/Immunology9191Allergy/Immunology99100Allergy/Immunology46%15%

Total199199Total6262

Specialty * Provide Drops and have patients on Crosstabulation

Count

Provide Drops and have patients onTotal

1.00

SpecialtyFamily Medicine77

Otolaryngology/ENT3333

Pediatrics22

NP/PA1010

Ophthalmology/Optometry11

Allergy/Immunology99

Total6262

Primary Benefits of Allergy DropsI17. What do you believe are the primary benefits of allergy drops over other treatments for allergies? Multiple Response. Base: Respondents who have received allergy drops, N=50*

Chart1

0.1670660994

0.1441885227

0.134335959

0.096597288

0.0704945603

0.0513884402

0.0316535435

0.0201503913

0.0201503913

0.019694786

0.017948602

0.2470761303

0.0315915238

Sheet1

No benefits17%

Convenient14%

Effective relief from allergies13%

No/fewer side effects10%

Long lasting7%

Fast acting/quick relief5%

Can customize for specific allergens3%

Insurance coverage2%

Builds up immune system2%

No need for other allergy medicines2%

Prevent other allergies and/or asthma2%

Don't know25%

Refused3%

ResponsesPercent of Cases

NPercent

712.2%13.5%0.134335959

$dropos172 Frequencies46.4%7.1%0.0704945603

22.9%3.2%0.0316535435

713.1%14.5%0.1441885227

dropos172aEffective relief from allergies11.8%2.0%0.0201503913

Long lasting11.8%2.0%0.019694786

Can customize for specific allergens11.6%1.8%0.017948602

Convenient24.5%5.0%0.0494934494

Insurance coverage815.2%16.8%0.1670660994

No need for other allergy medicines1222.4%24.9%0.2470761303

Prevent other allergies and/or asthma22.9%3.2%0.0315915238

Other (SPECIFY)"11.8%2.0%0.0201503913

No benefits58.8%9.7%0.096597288

(VOL) Don't know34.7%5.2%0.0513884402

(VOL) Refused55100.0%111.1%

**Builds up immune system

**Less/no side effects

**Fast acting/quick relief

Total

Primary Drawbacks of Allergy DropsI18. What do you believe are the primary drawbacks of allergy drops over other treatments for allergies? Multiple Response. Base: Respondents who have received allergy drops, N=50*

Chart1

0.2513037731

0.2037730527

0.2

0.1381596874

0.0477813207

0.017948602

0.015313953

0.1291402386

Sheet1

Inconvenient25%

Expensive/lack of insurance coverage20%

Not effective/temporary results20%

No drawbacks14%

Safety concerns5%

Don't like drops2%

Too invasive2%

Don't know13%

$I18 Frequencies

Responses

NPercentPercent of Cases

I18 dropsaToo invasive11.20%1.50%0.02

Inconvenient1219.80%24.30%0.24

Expensive/lack of insurance coverage1016.60%20.40%0.2

Don't like shots/drops11.50%1.80%0.02

Safety concerns23.90%4.80%0.04

Other (SPECIFY)2235.20%43.20%0.44

No drawbacks711.30%13.80%0.14

(VOL) Don't know610.50%12.90%0.12

Total61100.00%122.80%

a. Group

$dropsneg Frequencies

ResponsesPercent of Cases

NPercent

dropsnegaToo invasive11.5%

Inconvenient1325.1%

Expensive/lack of insurance coverage1020.4%

Don't like drops11.8%

Safety concerns24.8%

No drawbacks713.8%

Don't know612.9%

Not effective/temporary results1020.0%

Whats the Bottom-line?

Why has it been so hard to get SLIT approved by the FDA in the USA?

How SLIT studies differ from allergy and asthma medication studies?Not dealing with just population variation but allergen exposure variationPatients arent symptomatic prior to treatmentPollen levels vary and may not see as much variation in symptoms between groupsTotal composite scores-symptom improvement and medication decreaseSymptom scores-nose and eyeMedication scores-no standardized way to evaluate

FDA Requirements for SLIT are not clearFDA will probably require more efficacy than p

Sublingual Immunotherapy TechniquesSublingual-swallow Allergen Immunotherapy TabletOrosoluble tablet Northern grassesRagweed

Sublingual-swallow

A Randomized, Double-Blind, Placebo-Controlled, Parallel Trial of Standardized Short Ragweed (RW)Sublingual Allergy Immunotherapy Liquid (SAIL) Extract in Adult Subjects with Ragweed-Induced Allergic Rhinoconjunctivitis Peter S. Creticos, MDPhase IIIRagweed extract in 429 patients ages 18-55 with 2 year history of moderate to severe rhinoconjunctivitisSelf-administered RW-SAIL (target maintenance dose: 42 units Amb a 1 daily) or placebo (PL) [1:1 ratio] started 816 weeks prior and continued through the 2011 RW season. Three step process-placebo, 18 units Amb a 1, and 50 units Amb a1 Pts maintained daily symptom and rescue medication e-diaries. Efficacy endpoints included total combined symptom + medication scores (TCS), daily symptom scores (DSS), IgG4 and IgE ragweed-specific antibodySafety was evaluated by AE diaries/lab tests/physical exams

Allergen Immunotherapy Tablets

Timothy Grass AITNelson HS, Nolte H, Creticos P, Maloney J, Bernstein DI. Efficacy and Safety of Timothy Grass Allergy Immunotherapy Tablet Treatment in North American Adults. JACI Jan 2011; 127(1):72-80

Blaiss M, Maloney J, Nolte H, Gawchik S, Yao R, Skoner DP. Efficacy and Safety of Timothy Grass Allergy Immunotherapy Tablet Treatment in North American Children and Adolescents. JACI Jan 2011; 127(1):64-71

Symptom and Medication ScoringDaily Symptom Score (DSS; Maximum=18)Daily Medication Score (DMS; Maximum=36)*Symptoms: 0=none; 1=mild; 2=moderate; 3=severe*One tablet per day ; 1 drop per affected eye twice daily; 2 sprays in each nostril once daily; up to 10 tablets per day.

Rescue MedicationScore/Dose UnitMaximumDaily ScoreLoratadine 10-mg tablet*6 points/tablet6Olopatadine HCl 0.1% ophthalmic solution1.5 points/drop6Mometasone furoate nasal spray 50 g2 points/spray8Prednisone 5-mg tablet1.6 points/tablet16

Individual SymptomsMaximum Daily Score*Runny nose3Blocked nose3Sneezing3Itchy nose3Red/itchy/gritty eyes3Watery eyes3

Total Combined Symptom and Medication Scores:All Sensitization Types Grouped26% relative reduction in mean total combined score (TCS)*P=0.001

20%P=0.00521%P=0.01Reduction in TCS Relative to PlaceboWorseBettern=207n=184n=201n=183Nelson H, Nolte H, et al. Journal Allergy Clin Immuno 127:72-80, 2011.

Chart1

6.395.080.40.4

7.315.760.50.5

Placebo

Grass AIT

Adjusted Mean Score + SE

Sheet1

Entire GPSPeak GPSentire SEpeak SE

Placebo6.397.310.40.5

Grass AIT5.085.760.40.5

Treatment-Related Adverse Events in 5% of SubjectsMost treatment-related adverse events were transient oropharyngeal reactionsLocal oropharyngeal reactions rarely (

Grass AIT Was Well ToleratedThe vast majority (96%) of subjects with treatment-related adverse events reported them to be of mild or moderate severitySystemic allergic reactions and use of epinephrine were seldom observedDecember 6, 2011*World Allergy Congress

Adult StudiesPediatric StudiesGrass AIT(n=1060)Placebo(n=1036) Grass AIT(n=302)Placebo(n=296) Treatment-related adverse event, n (%)Any742 (70%)236 (23%)188 (62%)80 (27%)Severe31 (3%)8 (1%)3 (1%)0 (0%)Systemic allergic reaction, n (%)5 (

J Allergy Clin Immunol 2012;130:1327-34

A 5-grass pollen allergen extract (Cocksfoot , Sweet vernal grass , Rye grass , Meadow grass and Timothy )

Persistence with Specific Immunotherapy (SCIT & SLIT) Among AR Patients in A US Allergy Practice

Anolik et al AAAAI San Antonio 2013Methods: Data from a retrospective chart review study of allergic rhinitis patients managed at a group allergy practice in the US initiating subcutaneous immunotherapy (SCIT) or sublingual immunotherapy (SLIT) from 2005-2011 were analyzed.

ResultsA total of 3,182 patients were identified, 78% chose SCIT and 22% chose SLIT.Only 32.5% of patients completed treatment; 35% of SCIT and 23.7% of SLIT patients. Median time on therapy was longer for SCIT patients (3.6 years) versus SLIT patients (2.6 years). The full treatment course was completed by 30.2% of adult patients. The median time on treatment was substantially greater for adult patients on SCIT compared to SLIT (3 vs.1.6 years, respectively). Similar patterns were seen among children

Should all patients on SLIT have a auto-injector of epinephrine available for use? If so, why?

Since treatment is done at homeThere is a risk potential risk of anaphylaxisMedical-legal concernsNo deaths from AIT; mild systemic reactions onlyImproper use of epinephrine by the patientNot required in Europe and UKMost allergists in US do not require auto-injectors for patients on SCIT

YesNo

What are the Cost issues with SLIT in the US?Since approved SLIT will be by prescription, coverage may be dramatically different than coverage for SCIT that is prepared and billed by the allergistCosts will effect adherence to SLITde-Olano et al. Annals Allergy 2013 looked at adherence pre and during the recent Spanish recession and showed a significant decrease in SCIT and SLIT adherence during the recession With the changes in healthcare, will IT be covered as well as the past?Will there be a difference in SCIT vs SLIT in coverage?

ConclusionsWith both grass tablets and ragweed in review by the FDA, we should know within the next 2 months if approved for the USWill allergists and others in the US use these new treatments, continue to mix their own SLIT (without clinical data), or only continue SCIT? Financial aspects are importantAllergists-income on SCITChanges in healthcare-coverage for SLIT and SCIT

**********Key-messages: a 37% reduction in rhinoconjunctivitis symptoms in addition to the placebo effecta 41% reduction in the use of symptomatic medications in addition to the placebo effect *In adults, there were 5 investigator assessed likely systemic allergic reactions (4 mild, 1 moderate) to AIT treatment (0.01 events/subject treatment year) and 1 AIT-related sponsor-assessed possible systemic reaction (severe diarrhea and mild hives under the tongue).In children, there were no events diagnosed by investigators as likely systemic allergic reactions, but 4 AIT-related possible systemic reactions were observed based on sponsor assessment (moderate dyspnea and swollen tongue; moderate urticaria; moderate dyspnea with mild pruritus; mild flushing with moderate vomiting).*