The Current Status of Sublingual Immunotherapy

Transcription

1 The Current Status of Sublingual Immunotherapy Harold S. Nelson, MD Professor of Medicine National Jewish Health and University of Colorado Denver School of Medicine Denver, Colorado

2 Disclosure: Harold S. Nelson MD Below I have disclosed relevant commercial associations that might pose a conflict of interest Consultant Arrangements: Merck Circassia Stock/Other Equity Ownership: None Patent Licensing Arrangements: None Grants/Research Support: Circassia Speakers' Bureau: None

3 The Current Status of Sublingual Immunotherapy: Learning Objectives Upon completion of this session the attendee should: 1) Understand that many aspects of sublingual immunotherapy have been carefully investigated. 2) However, there are still major information gaps regarding dosing of liquid preparations and effectiveness of multiple allergen mixes.

4 Which of the following does NOT characterized SLIT therapy A. Efficacy in allergic asthma B. Prevention of further sensitization in monosensitized subjects. C. Absence of systemic adverse reactions D. Persisting benefit after discontinuation E. Defined dosing for grass, ragweed and house dust mite tablets.

5 Present Status of Sublingual Immunotherapy Documented: Efficacy with monotherapy for allergic rhinitis and allergic asthma Optimal duration Prevention of new sensitization and progression to asthma. Persistent benefit after stopping Appropriate dosing for SLIT tablets for grass, ragweed and house dust mite Improved safety in comparison with SCIT

6 Long-lasting Effects of sublingual Imunotherapy According to its Duration: A 15-year Prospective Study M Marogna, et al. J Allergy Clin Immunol 2010;126: monosensitized patients were treated with house dust mite extract by SLIT with a cumulative dose 30X the customary SCIT dose. Initial treatment was for 3, 4 or 5 years. When group symptom scores rose above 50% of baseline the group was retreated. Total duration of observation was 15 years.

7 A 15-year Prospective Study After stopping treatment relapse and retreatment occurred in 7 years in the 3-year group and 8 years in the 4-year and 5-year groups. The second course of SLIT produced more rapid improvement than the first in all three groups. Methacholine sensitivity and nasal eosinophils paralleled the clinical symptoms. M Marogna, et al. J Allergy Clin Immunol 2010;126:969-75

8 Symptom/Medication Scores Control Group A 3-years B 4-years C 5-years 100 SLIT SLIT JACI 2010

9 Percentage of Nasal Eosinophils SLIT3 SLIT4 SLIT5 CONTROLS 40 Nasal Eosinophils % NS NS NS NS 10 JACI :

10 Methacholine PD 20 SLIT3 SLIT4 SLIT5 CONTROLS 1000 Methacholine PD NS NS NS 200 NS JACI :

11 % Percent of Patients with New Prick Skin Test Reactions SLIT3 SLIT4 SLIT5 CONTROLS Significant from this point onward 20 JACI :

12 Immunotherapy Dosing with SLIT Grass Tablets N= 855 patients N= 628 patients 30 Placebo 100 IR IR 500 IR ,500 SQ-T 25,000 SQ-T 75,000 SQ-T Symptom score Medication score SQ-T = 17mcg Phl p IR ~ 8mcg Gp p 5, 300IR ~ 25mcg Gp p 5 Durham SR, JACI 2006;117:802-9 Didier et al. JACI 2007;120:

13 Ragweed Sublingual Immunotherapy Tablets Dosing (TCS Active vs. Placebo) Subjects 1 mcg Amb a 1 6 mcg Amb a 1 12 mcg Amb a 1 Creticos (2013) 784 9% p = % P = % p = Nolte (2013) % p = % P < 0.001

14 SQ HDM SLIT-Tablets Contains 7.5 mcg of each major allergen (total 30 mcg). Monthly dose about 50X SCIT maintenance dose. Der p 1 Dermatophagoides pteronyssinus Der p 2 Der f 1 Group 1 Der f 2 Group 2 Dermatophagoides farinae

15 Onset and dose-related efficacy of house dust mite sublingual immunotherapy tablets in an environmental exposure chamber H Nolte, J Maloney, HS Nelson, DI Bernstein, S LU, Z LI, et al. J Allergy Clin Immunol 2015;135: subjects with HDM allergic rhinitis +/- asthma. Treated with HDM SLIT-tablets 6 DU (7.5 μg Gp 1), 12 DU (15 μg Gp 1) or placebo daily for 24 weeks. Assessed in Vienna Environmental Exposure Chamber for 6 hours at baseline, and after 8, 16 and 24 weeks.

16 Average TSS (Nasal + Ocular) During Hours 2-6 of the Challenge Average TSS (LS Mean) % 16.0% 23.2% 28.6% 30.5% 52.2% Week 8 Week 16 Week 24 Worse Placebo MK DU MK DU Better Except for 6 DU at 8 weeks, all active groups are significantly different from placebo H Nolte, et al. J Allergy Clin Immunol 2015;135:

17 Efficacy and Safety of the SQ House Dust Mite Sublingual Immunotherapy Tablet in North American Children and Adults: Findings from a Large Randomized, Placebo-Controlled Clinical Trial Nolte, H.; Bernstein, D.I. Kleine-Tebbe, J.; Sussman, G.L.; Seitzberg, D. Rehm, D.; Kaur, A.; Li, Z.; Lu, S.; Nelson, H.S. J Allergy Clin Immunol 2016 (in press) 1482 Subjects with perennial allergic rhinitis (79% completed study) 31% with a history of asthma 68% with a history of seasonal allergic rhinitis

18 Inclusion criteria 12 years of age Sensitization to D. pteronyssinus and/or D. farinae with both: Skin prick test wheal size 5 mm larger than saline control Serum-specific IgE 0.7 ku/l Total rhinitis daily symptom score of 6/12, or 5 with 1 symptom being severe, on 5 of 7 consecutive days before randomization Exclusion criteria Key Eligibility Criteria History of symptomatic perennial or seasonal AR/C to an allergen which potentially overlapped with run-in and efficacy assessment periods Severe asthma (<70% FEV 1 predicted) or unstable asthma AR/C=allergic rhinitis with/without conjunctivitis

19 Trial Objective and Design To evaluate the efficacy and safety of SQ HDM SLIT-tablet in North American subjects with HDM allergic rhinitis with/without conjunctivitis Induction treatment; ~31 weeks Efficacy Assesessment; 8 weeks 12 SQ-HDM (n=741) Screening HDM skin prick test HDM serum specific IgE FEV 1 70% predicted Placebo (n=741) Randomization Initiation of study drug observed in the clinic

20 12 SQ-HDM Improved TCRS, Rhinitis DSS, and TCS vs Placebo 17% Worse 17% % % TCRS Rhinitis DSS Rhinitis DMS TCS (Ocular- Nasal) Plots are median (upper/lower quartiles) except for rhinitis DMS, which are estimated means (95% CI) Nominal P-values <0.001 vs placebo 95% CI: 10%, 25% Percentages represent treatment difference relative to placebo Better

21 Effect of HDM SLIT-Tablet on Asthma

22 SQ HDM SLIT-tablet in Treatment of Asthma Post hoc Results from a Randomised Trial. F de Blay et al. Respir Med 2014;108: From a DB, PC trial of 6 DU HDM tablet in 604 subjects with asthma, performed a post hoc analysis on 108 subjects with partially controlled asthma: - Daily ICS dose mcg/day and - ACQ score of After one year, compared to placebo, HDM SLIT-tablet patients: - Had reduced daily ICS use by 327 mg/ (p < ) - Had improved AQLQ of 0.52 (p = 0.01)

23 Efficacy of a House Dust Mite Sublingual Allergen Immunotherapy Tablet in Adults with Allergic Asthma: A randomized trial JC Virchow, et al. JAMA;315: adults with HDM-related asthma not well controlled on ICSs were randomized to 12 months treatment with placebo, 6 SQ or 12 SQ HDM SLIT tablets. After 6 months ICS dose was reduced 50% and after 9 months ICSs were withdrawn complete. Primary outcome time to first moderate/severe exacerbation during ICS withdrawal.

24 Efficacy of a House Dust Mite Sublingual Allergen Immunotherapy Tablet in Adults with Allergic Asthma: A randomized trial Exacerbations occurred in 26% on 6-SQ, 24% on 12 SQ and 32% on placebo. Hazard ratio: 6 SQ was 0.72 (95% CI ) P = SQ was 0.69 (95% CI ) P = 0.03 JC Virchow, et al. JAMA;315:

25 Probability of having the First Moderate/Severe Asthma Exacerbation 35 50% ICS Reduction 100% ICS Reduction Probability of First Moderate or Severe Asthma Exacerbation, % Placebo 6 SQ-HDM tablet 12 SQ-HDM tablet 0 Beginning of Period Time During ICS Reduction, d No. at risk Placebo 6 SQ-HDM tablet 12 SQ-HDM tablet JC Virchow, et al. JAMA 2016;315:

26 Efficacy and Safety of Sublingual Tablets of House Dust Mite Allergy Extracts: Results of a Dose-ranging Study in an Environmental Exposure Chamber M Roux, P Devillier, WH Yang, A Montagut, K Abiteboul, A Viatte, RK Zeldin. J Allergy Clin Immunol 2016;138:451-8 A randomized, double-blind, placebo controlled trial in 355 participants with perennial rhinitis and sensitivity to house dust mite. Subjects received one of three doses of HDM SLIT tablets or placebo daily for 6 months. Outcome: Symptoms in an Environmental Exposure Chamber over 4 hours.

27 Efficacy and Safety of Sublingual Tablets of Baseline Challenge House Dust Mite Allergy Extracts Month 1 Challenge Month 2 Challenge Month 4 Challenge Month 6 Challenge Primary Screening Randomization N=355 Placebo, N=87 Follow-up visit 100IR, N=89 300IR, N=86 500IR, N=93 Within 8 weeks 6 treatment months ~2 weeks M Roux, et al. J Allergy Clin Immunol 2016;138:451-8

28 Efficacy and Safety of Sublingual Tablets of House Dust Mite Allergy Extracts Index of Reactivity Der p 1 Der f 1 Monthly dose compared to SCIT 100 IR 4-6 μg μg 88 X 300 IR μg μg 258 X 500 IR μg μg 434 X M Roux, et al. J Allergy Clin Immunol 2016;138:451-8

29 Total Rhinitis Symptom Score over 4 Hours in the Environmental Exposure Chamber 9 At baseline 9 After 6 treatment months RTSS Least Squares mean Standard Error Time (hours) Time (hours) Placebo 100IR 300IR 500IR M Roux, et al. J Allergy Clin Immunol 2016;138:451-8

30 Efficacy and Safety of Sublingual Tablets of House Dust Mite Allergy Extracts Change from baseline in AUC Rhinitis Total Symptom Score versus placebo Index of Reactivity AUC RTSS 0-4 Hours AUC RTSS 2-4 Hours 100 IR 19.8% (N.S.) 30.5% (N.S.) 300 IR 28.8% (N.S.) 40.9% (p = ) 500 IR 33.2% (p = % (p = ) Discontinuation due to adverse events: 12% for 500 IR and 6% for 300 IR and 100 IR. No severe local reactions, no anaphylaxis, no use of epinephrine. M Roux, et al. J Allergy Clin Immunol 2016;138:451-8

31 House Dust Mite Sublingual Tablet is Effective and Safe in Patients with Allergic Rhinitis Y Okamoto, et al. Allergy 2016;e-pub ahead of print 968 Japanese subjects age years with perennial rhinitis, HDM-specific IgE 0.7 Ua/mL, positive nasal provocation test and average rhinitis total symptom score 6/15 for 7 days before randomization. Treated with SLIT placebo, 300 IR or 500 IR for 52 weeks. Dose (Der p 1 + Der f 1) 300 IR 84 μg & 500 IR 148 μg.

32 Response to HDM Tablets in Perennial AR Average Adjusted Symptom Score (AASS) Baseline W8-10 W16-18 W24-26 W32-34 W40-42 W IR 500 IR Placebo % % Time (Week) Y Kamoto, et al. Allergy 2016e-pub ahead of print

33 Adverse Reactions to Grass SLIT Summary of 7 Phase III Studies Adults (n=2096) Children (n=598) AIT Placebo AIT Placebo Oral Pruritus 39% 5% 35% 3% Throat Irritation 21% 3% 25% 2% Ear Pruritus 14% 1% 8% <1% Mouth Edema 11% <1% 8% <1% Oral Paresthesias Any Drugrelated 8% 1% 70% 23% 62% 27% Abstract EAACI June 2011

34 Onset and Duration of Adverse Reactions to Grass SLIT (Median Days) Adults Onset (day) Duration (days) Children Onset (day) Oral Pruritus Throat Irritation Ear Pruritus Oral Paresthesias 1 10 Duration (days) Mouth Edema Abstract EAACI June 2011

35 Systemic Reactions in US Slit-Tablet Trials 1501 subjects received 17 μg timothy tablet or placebo for about 20 weeks: - 2 moderate systemic reactions with timothy subsided without treatment. - 1 systemic reaction with placebo. J Maloney, et al. Ann allergy Asthma Immunol 2014;112: subjects received 12 DU ragweed and 757 placebo tablets for 4 or 52 weeks. - 1 systemic with active treatment, self-administered epinephrine - 1 with placebo in latex sensitive subject treated with epinephrine. H Nolte, et al. Ann Allergy Asthma Immunol 2014;113:

36 Epinephrine Use in clinical Trials of Sublingual Immunotherapy Tablets. H Nolte, et al. J Allergy Clin Immunol Pract (in press) Data was collected on epinephrine use in clinical trial development program of 3 sublingual tablets (timothy, ragweed and house dust mites). 8,152 subjects received active treatment, 6,799 the final approved doses and 5,155 received placebo. 25 on active treatment received epinephrine, 16 for SLIT-related events, while 10 placebo-treated received epinephrine.

37 Epinephrine Use in clinical Trials of Sublingual Immunotherapy Tablets. Number Subjects Grass Epinephrine use (Active) Epinephrine use (Placebo) SLIT-related systemic reactions 4, (all day one) 4 Ragweed 2, ( One subj) 1 (day six) 3 HDM 6, (day one) 3 SLIT-related Local Reactions None of the SLIT-related reactions fit the FDA criteria for serious H Nolte, et al. J Allergy Clin Immunol Pract (in press)

38 Use of Epinephrine Auto-injectors in U.S. SLITtablet Trials: Summary Epinephrine was provided to most participants in U.S. trials (n=6,427) There were 13 self-administrations 5 were for SLIT-tablet related events 1 was for a systemic reaction and 4 were for local reactions. None of the 5 reactions met the FDA criteria for Serious H Nolte, et al. J Allergy Clin Immunol Pract (in press)

39 Esophageal Hypereosinophilia Induced by Sublingual Immunotherapy There are two well documented cases reports of biopsy-proven eosinophilic esophagitis one induced by timothy grass SLIT-tablets and one by liquid SLIT with birch/hazel nut/alder extract. Both responded to cessation of SLIT, one recurred with a second challenge. A history of EOE is a contraindication to starting SLIT-tablets (FDA). S Miehlke, et al. Case Rep Gastroenterol 2013;7: ; A Antico, R Fante, J Allergy Clin Immunol 2014;133:1482-4

40 Problems with Sublingual Immunotherapy 1) Poorly-defined doses for liquid extracts 2) Lack of demonstrated efficacy for simultaneous administration of more than two unrelated extracts. 3) Prolonged duration of therapy (3-5 years) 4) Poor long-term adherence 5) Efficacy versus SCIT?

41 Which of the following is true regarding SLTT with liquid extracts? A. European commercial SLIT products provide reliable guidance for SLIT-liquid dosing. B. Effective treatment is generally achieved with a cumulative monthly dose times the recommended SCIT maintenance dose C. Up to 10 unrelated extracts can be coadministered without compromising efficacy. D. Effective doses have been defined by multiple dose studies for most standardized extracts. E. There are no clinical trials to support the efficacy of many European commercial SLIT products.

42 Dosing of European Sublingual Immunotherapy Maintenance Solutions Relative to Monthly Recommended Dosing of Subcutaneous Immunotherapy Desiree Larenas-Linnemann, Ralph Mosges Allergy Asthma Proc 2016;37:50-56 Assayed the potency of 3 European companies SLIT preparations for HDM, timothy, cat and ragweed. Monthly cumulative SLIT dosing compared to mid-range of SCIT doses recommended in Immunotherapy Practice Parameters III

43 Dosing of European SLIT Solutions Relative Company 1 Monthly dose X SCIT dose Company 2 Monthly dose X SCIT dose Stallergenes Monthly dose X SCIT dose to Monthly Recommended Dosing of Subcutaneous Immunotherapy D. Pt AU 1440 AU 1 X 3180 AU 3 X 15,870 AU 16 X Entries in red have studies showing efficacy. Timothy BAU 41,550 BAU 21 X 113,250 BAU 57 X 187,200 BAU 94 X Cat Fel d 1 μg 4.8 Fel d 1 U 1 X 50.4 Fel d 1 U 13 X 117 Fel d 1 U 31 X Ragweed Amb a 1 μg 378 Amb a 1 U 42 X 615 Amb a 1 U 68 X 2136 Amb a 1 U 237 X Desiree Larenas-Linnemann, Ralph Mosges Allergy Asthma Proc 2016;37:50-56

44 Variation in Allergen Content in Liquid Sublingual Allergen Immunotherapy with Dust Mites F Moreno Benitez, M Espinazo Romeu, A Letran Camacho Allergy 2015;70: Compared the 5 most relevant SLIT-HDM liquid products on the Spanish market. Quantified Der p1, Der f 1, and Group 2 allergens. Reported data of efficacy were scarce for most of the 5 products

45 Variation in Allergen Content in Sublingual Allergen Immunotherapy (SLIT) with Dust Mites (HDM) Results HDM-SLIT extract Dosing frequency Monthly Der p 1 (μg) Monthly Der f 1 (μg) Monthly Group 2 (μg) SLITone Ultra ALK-Abello Staloral Stallergenes Sublivac HAL Allergy Sublingual Allergovac Plus Bial-Aristegui TOL Forte Leti Daily times weekly Daily times weekly Daily F Moreno Benitez, et al. Allergy 2015;70:

46 Liquid SLIT Dosing: Recent/Large Studies Allergen Author Subjects SLIT dose SCIT Dose Dose Ratio Clinical response (SLIT) Grass Ott (2009) 183 Adults & children 21 μg Daily 20 μg Monthly 32 X 1 st season S 34% M 14% Wahn (2012) 207 children 40 μg Daily 60 X One season S/M 26% Ragweed Creticos (2014) 429 Adults 50 μg Daily 12 μg Monthly \ 125 X One season S/M 20% Birch Pfaar (2016) 269 Adults 47 μg daily 24 μg 15 μg Monthly 94 X 47X P<.001 NAC P =.07 HDMs Bozek (2013) 96 elderly 150 μg Group 1 5/week 8.5 μg Monthly 383 X 3 rd year S 33% M 26% Wang (2014) 465 Adult asthma 78 μg Group 1/day 279 X One year Control ICS

47 Liquid SLIT Dosing: Recent/Large Studies Allergen Author Subjects SLIT dose SCIT Dose Dose Ratio Clinical response (SLIT) Grass Ott (2009) 183 Adults & children 21 μg Daily 20 μg Monthly 32 X 1 st season S 34% M 14% Wahn (2012) 207 children 40 μg Daily 60 X One season S/M 26% Ragweed Creticos (2014) 429 Adults 50 μg Daily 12 μg Monthly 125 X One season S/M 20% Birch \ Pfaar (2016) 269 Adults 47 μg daily 24 μg 15 μg Monthly 94 X 47X P<.001 NAC P =.07 HDMs Bozek (2013) 96 elderly 150 μg Group 1 5/week 8.5 μg Monthly 383 X 3 rd year S 33% M 26% Wang (2014) 465 Adult asthma 78 μg Group 1/day 279 X One year Control ICS

48 S M. Amar, RJ Harbeck, M Sills, LJ Silviera, H O Brien, HS Nelson J Allergy Clin Immunol 2009;124:150-6

49 Single-center, randomized, double-blind, placebo-controlled. SLIT for 10 months, 56 subjects randomized to 3 arms - SLIT with timothy pollen extract alone (17 mcg Phl p 5 daily) - SLIT with same dose of timothy extract + 9 additional pollen extracts - SLIT placebo SM Amar, et al. J Allergy Clin Immunol 2009;124:150-6

50 MAT Group, Allergen Extract Timothy Maple, Box-Elder Ash, White Juniper, Western Elm, American Cottonwood, Common Firebush (Kochia) Ragweed, Western Sagebrush, Common Russian Thistle Amount added to 10 ml vial for 1 month of treatment Amount 1.0 ml 1.0 ml 1.0 ml 1.0 ml 1.0 ml 1.0 ml 1.0 ml 1.0 ml 1.0 ml 1.0 ml TM Group, Allergen Extract Timothy Diluent Caramelized Sugar Placebo Group Diluent Caramelized Sugar SM Amar, et al. J Allergy Clin Immunol 2009;124:150-6 CMD : Timothy approximately 30x SCIT dose (17 mcg Phl p 5 q day), other allergens 15-20x SCIT dose Amount 1.0 ml 9.0 ml Amount 10 ml

51 Multi-allergen Sublingual Immunotherapy: Results Changes with active treatment compared to placebo Outcome Titrated Nasal Challenge Timothy Monotherapy P = 0.02 Timothy Multiallergen N.S. Titrated Prick Skin Test P < P = 0.03 Timothy-specific IgG4 P = N.S. SM Amar, et al. J Allergy Clin Immunol 2009;124:150-6

52 Direct Comparisons of SCIT and SLIT 11 randomized studies, 4 double-blind, 7 open. Favors Symptoms or Combined Scores Medication Scores Immunologic & Challenge Outcome (number of studies) SCIT only over Placebo 4 (SCIT significantly superior to SLIT in 2) 2 (SCIT significantly superior to SLIT in 1) PST (3), IgG4(7), BAC(1), NAC (1) Neither or Both over Placebo SLIT only oven Placebo 7 2 PST (2), NAC (2) Difficulties in comparison: SLIT often low-dose and often three times weekly. HS Nelson. JACI in Practice 2014;2:144-9

53 Immunological Comparison of Allergen Immunotherapy Tablet Treatment and Subcutaneous Immunotherapy Against Grass Allergy K Aasbjerg, et al, et al Clin Exp Allergy 2014;44: grass pollen allergic patients received SCIT, SLITtablet, or neither for 15 months. SLIT dose 75,000 SQ-U daily; SCIT dose build-up then 100,000 SQ-U every 2 months. Nasal challenge assessed clinical response Measured antibodies and competition assays.

54 Symptoms with Nasal Challenge (SLIT vs. SCIT) Greyed areas are 95% confidence intervals Nasal challenge total symptom score x P < 0.05 SCIT vs. SLIT & Control x x P < 0.05 SCIT vs. Control Months after treatment start treatment control SLIT tablet SCIT Grass pollen season x K Aasbjerg, et al CEA 2014;44:417-28

55 IgG4 Response SLIT vs. SCIT 2.0 Greyed areas are 95% confidence intervals Log(IgG4 to Phleum pratense (mga/l)) x x x x ; x ; ; x x ; x ; ; x ; x Months after treatment start treatment control SLIT tablet SCIT Grass pollen season x K Aasbjerg, et al. Clin Exp Allergy 2014;44:417-28

56 Real-life Compliance and Persistence Among Users of Subcutaneous and Sublingual Allergen Immunotherapy MA Kiel, et al. J Allergy Clin Immunol 2013;132: A community pharmacy database from the Netherlands was examined for patients starting immunotherapy between 1994 and ,796 received SCIT and 3,690 SLIT 3-years of treatment completed by 23% with SCIT and 7% with SLIT Mean duration of persistence: SCIT 1.7 years and SLIT 0.6 years (p <.001)

57 Sublingual Immunotherapy: Answered and Unanswered Questions Answered: 1) Efficacy in allergic rhinitis and allergic asthma 2) Dosing with SLIT-tablets 3) Optimal duration 4) Disease modification 5) Improved safety over SCIT. Unanswered: 1) Dosing with liquids 2) Efficacy of multiple allergen mixes 2) Efficacy versus SCIT 3) How to improve long-term adherence