Workgroup: Immunotherapy Options for Treatment of Allergic Asthma - - PowerPoint PPT Presentation

Workgroup: Immunotherapy Options for Treatment of Allergic Asthma

Addressing Disparities Program June 30, 2015

Welcome to PCORI

Please be seated by 9:55 AM. Webinar will begin at 10:00 AM.

• Restrooms are located outside near the elevators. Key fobs are

available at our front desk.

• This webinar is public so please state your name and title before

speaking.

• Where possible, we encourage you to avoid acronyms in your

discussion of these topics.

• Please stand your name tent up to let the moderator know that

you are interested in speaking.

• To use the push-to-talk microphones, please press the button
• n the lower right-hand side and speak into the microphone

when red circle lights up around microphone.

Information for Workgroup Participants

3

Welcome and Introductions

Romana Hasnain-Wynia, PhD, MS Program Director, Addressing Disparities

4

Today’s webinar is open to the public and is being recorded.

• Members of the public are invited to listen to this webinar.
• Topic brief, agenda, and other materials are available on the

PCORI site.

• Comments may be submitted via chat. No public comment

period is scheduled today.

For those on the phone

• If you experience any technical difficulties, please alert us via

chat or email support@meetingbridge.com.

Housekeeping

Introductions: Moderator and Chair

Sandra Y. Lin, MD Associate Professor Johns Hopkins School of Medicine Department of Otolaryngology-Head & Neck Surgery

6

Welcome

• Please introduce yourself
• State your name and affiliation

Introductions: Workgroup Participants

Alkis Togias, MD Branch Chief, Allergy, Asthma and Airway Biology Division of Allergy, Immunology, and Transplantation National Institute of Allergy and Infectious Diseases National Institutes of Health

8

Introductions: Workgroup Participants

Lynn Morrison President Washington Health Advocates Representing the American Academy of Allergy, Asthma and Immunology

9

Introductions: Workgroup Participants

Jonca Bull, MD Assistant Commissioner for Minority Health U.S. Food and Drug Administration

10

Introductions: Workgroup Participants

Bridget Smith, PhD Research Associate Professor, Pediatrics Northwestern University Feinberg School of Medicine

11

Introductions: Workgroup Participants

Tyra Bryant-Stephens, MD Director and Founder, Community Asthma Prevention Program Children’s Hospital of Philadelphia Clinical Associate Professor of Pediatrics University of Pennsylvania School of Medicine Representing American Academy of Pediatrics

12

Introductions: Workgroup Participants

Lisa A. Gilmore, MBA, MSW Senior Consultant

13

Introductions: Workgroup Participants

Peter S. Creticos, MD Associate Professor of Medicine Division of Allergy and Clinical Immunology Johns Hopkins School of Medicine Director, Creticos Research Group

14

Introductions: Workgroup Participants

Meryl Bloomrosen, MBI, MBA Senior Vice President Policy, Advocacy and Research Asthma and Allergy Foundation of America

15

Introductions: Workgroup Participants

Antonio Linares, MD Regional Vice President, Medical Director Anthem Blue Cross – Health and Wellness Solutions

16

Introductions: Workgroup Participants

Kim Marie Wittenberg, MA Health Scientist Administrator Agency for Healthcare Research and Quality Center for Evidence and Practice Improvement

17

Agenda

Time Item

10:00 AM Welcome and Introductions 10:15 AM Introduction to PCORI and Workgroup 10:30 AM Setting the Stage 11:30 AM Workgroup Participants’ Perspectives on Subcutaneous vs. Sublingual Immunotherapy 12:30 PM Lunch 1:00 PM Workgroup Discussion: Components of Comparative Effectiveness Trial(s) for Subcutaneous vs. Sublingual Immunotherapy for Allergic Asthma 2:00 PM Patient, System, and Community Factors for Conducting Trial on Subcutaneous

• vs. Sublingual Immunotherapy for Allergic Asthma

3:00 PM Break 3:10 PM Discussion and Consensus around Key Research Gaps 3:45 PM Identification and Refinement of Comparative Effectiveness Research Questions 4:45 PM Next Steps and Wrap-Up 5:00 PM Adjourn

18

Introduction to PCORI and Workgroup

Romana Hasnain-Wynia, PhD, MS Program Director, Addressing Disparities

19

• PCORI is an independent non-profit research organization that

aims to improve the quality and relevance of evidence to help patients, clinicians, employers and others make health decisions.

• We do this by funding patient-centered comparative

effectiveness research.

• Our research addresses questions most important to patients

and we involve patients and a range of stakeholders in everything we do – from topic prioritization to dissemination of

• ur work.

About PCORI

20

‘‘(c) PURPOSE —The purpose of the Institute is to assist patients, clinicians, purchasers, and policy-makers in making informed health decisions by advancing the quality and relevance of evidence…”

Patient Protection and Affordable Care Act (PPACA): Subtitle D of Title VI - Sec. 6301. (2010)

PCORI’s Mission Defined

• Be patient-centered: Is the proposed information gap of

specific interest to patients, their caregivers, and clinicians?

• Assess current options: What current guidance is available on

the topic and is there ongoing research? How does this help determine whether further research is valuable?

• Have potential for new information to improve care and

patient-centered outcomes: Would new information generated by research be likely to have an impact in practice?

• Provide information that is durable: Would new information on

this topic remain current for several years, or would it be rendered obsolete quickly by subsequent studies?

• Compare among options: Which of two or more options lead to

better outcomes for particular groups of patients?

Research Questions Should…

22

• Cost effectiveness: PCORI will not answer questions related to

cost-effectiveness, costs of treatments or interventions. However PCORI will consider the measurement of factors that may differentially affect patients’ adherence to the alternatives such as out-of-pocket costs.

• Medical billing: PCORI will not address questions about

individual insurance coverage or about coverage decisions from third party payers.

• Disease-processes and –causes: PCORI will not consider

questions that pertain to risk factors, origin and mechanisms

• f diseases or questions related to bench science.
• Lacking comparative nature or foundation: PCORI will not

consider questions that lack any comparative aspect.

Questions External to PCORI’s Mandate

23

PCORI’s Process for Identifying Research Topics and Gaps

Topics/Questions proposed for further consideration

Topics come from multiple sources Gap confirmation Priority topics/ questions (Multi-stakeholder Advisory Panels and Workgroups) (PCORI staff in collaboration with AHRQ and others) 1:1 interactions with stakeholders Guidelines development, evidence syntheses Website, staff, Advisory Panel suggestions Board topics Workgroups, roundtables

• Eliminating

non- comparative questions

• Aggregating

similar questions

• Assessing

research gaps

• Preparing topic

briefs

24

Addressing Disparities Program Mission Statement

Program’s Mission Statement

To reduce disparities in healthcare outcomes and advance equity in health and health care Program’s Guiding Principle To support comparative effectiveness research that will identify best options for eliminating disparities

PCORI’s Vision, Mission, Strategic Plan

25

• Identify high-priority research questions

relevant to reducing and eliminating disparities in healthcare outcomes

Identify Research Questions

• Fund comparative effectiveness research

with the highest potential to reduce and eliminate healthcare disparities

Fund Research

• Disseminate and facilitate the adoption
• f promising/best practices to reduce

and eliminate healthcare disparities

Disseminate Promising/Best Practices

Addressing Disparities: Program Goals

26

PCORI’s Investment in Asthma

• Our current cohort of asthma projects examine multi-level,

multi-component interventions to improve adherence to NAEEP guidelines

• Projects test a variety of strategies, many outside clinic
• Think: community health workers, improving patient-

provider communication, reducing triggers in the home, projects with community roots

Optimizing PCORI’s Investment in Asthma

Where we are… …Where we could go from here.

• Opportunity to round out current cohort with new tPFA on

narrow, clinical asthma topic that would: – Shed light on important question about treatment options – Leverage future findings from existing asthma portfolio (and vice versa)

Proposed Topic: Immunotherapy Options for Asthma Treatment

• Priority topic at NIH and AHRQ.

Evidence gap identified by AHRQ Comparative Effectiveness Review: Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma (March 2013)

• American Academy of Allergy,

Asthma and Immunology also identified topic as important gap

• Subcutaneous immunotherapy is used worldwide…
• Sublingual immunotherapy used broadly in Europe, Latin

America and Asia, but 3 tablets only recently approved in US!

• Meanwhile, increasing number of US docs use sublingual

immunotherapy “off-label”

• Increasing interest in sublingual immunotherapy as alternative

and patient-centered approach to subcutaneous – Does not require injections – Can be administered by patients at home Topic has BIG Potential for Influencing Practice and/or Policy in U.S. – *Important Context*

• Identify and refine clinical comparative effectiveness research

question(s) on immunotherapy options (i.e., subcutaneous and sublingual) for the treatment of allergic asthma.

Our Goal for Today

The Plan

• Step 1: Perspectives and insight from around the table

» Each workgroup participant will have a few minutes to share perspective on this research topic

• Step 2: Discuss key considerations for trial

» Discuss trial design and implementation: methods, intervention, population(s) and recruitment, cost and feasibility » Discuss patient, system, and community factors (e.g., clinical settings, community involvement) » Achieve consensus on most important evidence gaps

• Step 3: Identify and refine research question(s)

» Identify specific populations, setting, outcomes, etc. (PICOTS framework) » Consideration of PCORI criteria for research topics

32

• Participants in this workgroup will be eligible to apply for funding if PCORI

decides to produce a funding announcement.

• The Chair(s) of the workgroup will be eligible to apply for funding should

they not participate in any subsequent discussions with PCORI following the workgroup.

• Input received during the workgroup deliberations are broadcast via

webinar, and the webinar is then archived and available to other researchers, patients, or stakeholders on the website.

• PCORI does not have subsequent discussions with the participants after this

workgroup.

• Participants are expected to address a set of questions we’ve asked – not to

tell us about their research.

• There should be no “influence advantage” to being a workgroup member, or

any knowledge advantage by participating in the workgroup.

How PCORI Manages the Potential for Conflict of Interest

33

Immunotherapy for the Treatment of Allergic Asthma: Setting the Stage Sandra Y. Lin, MD

Johns Hopkins School of Medicine Department of Otolaryngology – Head and Neck Surgery

• Allergic rhinitis is an inflammatory,

IgE-mediated, disease characterized by nasal congestion, rhinorrhea (nasal drainage), sneezing, and/or nasal itching.

• Asthma is a chronic lung disease that

inflames/narrows the airways. Symptoms can include wheezing, chest tightness, shortness of breath, and coughing.

• Allergic asthma is asthma that can

have an allergic trigger.

Definitions

35

• 9% of Americans suffer from asthma, 230 million worldwide
• Asthma is the leading chronic disease in children and reason for

missed school days

• Cause for 2 million ER visits annually
• 62% of asthmatics show evidence of allergy (1 or more positive

allergy tests)

Healthcare Burden: Allergic Asthma

36

Immunotherapy

Only true hope of “cure” Disease Modulation

Avoidance Pharmacotherapy

Treatment Options for AR and Allergic Asthma

KAS 11: Immunotherapy

• Diagnosis is confirmed with specific IgE testing (skin testing or

blood testing).

• Inadequate response to environmental

controls/pharmacotherapy

• Patient preference
• Adherence to therapy
• Medication requirements/adverse effects
• Allergic asthma
• Prevention of asthma/new sensitivities

AAO-HNS Allergy Rhinitis CPG: Candidates for Immunotherapy

Otolaryngology -- Head and Neck Surgery February 2015 152: S1-S43, doi:10.1177/0194599814561600

• Allergen specific immunotherapy (IT)

– recognized as effective since early 1900’s – subcutaneous route most common in U.S. – immune system “modulation” to develop “tolerance” to environmental allergens

Allergen Immunotherapy

KAS 11: Immunotherapy

Subcutaneous Immunotherapy

• injections

Immunotherapy in the US

Sublingual Immunotherapy

• Aqueous
• Tablet
• Ragweed
• Timothy
• Grass Mix

• Dosed in physicians office

– Once/week first year

• Typical duration: 3-5 years of treatment
• Continued benefit after discontinuation of therapy
• How effective is SCIT?

Subcutaneous Immunotherapy (SCIT)

Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review

Lin SY, Erekosima N, Suarez-Cuervo C, Ramanathan M, Kim JM, Ward D, Chelladuria Y, Segal JB.

AHRQ Grant HHSA 290 2007 10061 AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality. March 2013.http://effectivehealthcare.ahrq.gov/ehc/products/270/1427/allergy-asthma-immunotherapy- 130802.pdf

This report was based on research conducted by the Johns Hopkins University Evidence- based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-2007-10061-I). The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services.

Disclaimer:

43

7/28/2015

• Objective: Systematically review the effectiveness and safety of

SCIT for allergic rhinitis and asthma

• Methods: RCTs comparing SCIT to placebo, medication, or
• ther SCIT

– English language – Adults and Children – Similar formulation must be available in the U.S. – Must contain direct clinical outcomes

Systematic Review: SCIT Effectiveness

44

Literature Search

Medline, Embase, Lilacs, Cochrane

Search from database inception to Dec 2012

abstracts

7,746

Full article

1804

Final included

74 RCTs 4,350 participants

45

Grading the Evidence

Category Definitions Consistency Overall consistency of the direction of change Directness Does this measure a direct clinical

• utcome (symptoms, medication use)?

Magnitude of Effect Percent difference pre/post to comparator:

• weak <15%
• moderate 15-40%
• strong >40%

Risk of Bias

• Random Allocation
• Allocation Concealment
• Inadequate Blinding
• Incomplete Data Reporting
• Sponsor Participation in Study Design

*from GRADE Working Group Guide for CER

Grading the Evidence

Evidence Grade Definition Criteria

High High confidence that evidence reflects true effect; further research unlikely to change confidence

• At least 2 low ROB, one with

strong MOE

• Overall evidence consistent

Moderate Moderate confidence that evidence reflects true effect; further research may change estimate

• 1 low ROB with Strong MOE,
• r
• 2 or more medium ROB with

strong MOE, or

• 1 low ROB with mod MOE

plus 1 medium ROB plus strong MOE Low Low confidence that evidence reflects true effect; further research likely to change estimate

• Does not meet the above

Insufficient Evidence unavailable

47

• Age Range: 3-72 years
• Children only studies:
• Risk of Bias Moderate (52%)
• Comparator groups

– Placebo 73% – Meds 9% Results

48

SCIT Results

Outcome

• No. Studies
• No. Participants

Strength of Evidence Asthma symptoms 16 1,178 High Asthma symptoms (children only) 6 550 Moderate

49

• Strong to moderate evidence supports the

effectiveness of SCIT for AR and allergic asthma SCIT SR Conclusion

50

• Safety data reported in 45/74 studies
• No consistent reporting system for adverse events—

cannot pool

• Local reactions: 5-58% patients/0.6-54% injections

– mild

• Systemic reactions: in 15% of injections

– Most commonly respiratory – Most mild

• Anaphylaxis: 13 reactions
• Deaths: none

SR: SCIT Safety

51

• Dosed at home
• Aqueous “Drops” FDA off label
• Tablets: FDA Approval April 2014

Sublingual Immunotherapy in the United States

Sublingual Immunotherapy for the Treatment

• f Allergic Rhinoconjunctivitis and Asthma:

A Systematic Review

Lin SY, Erekosima N, Kim JM, Ramanathan M, Suarez-Cuervo C, Chelladurai Y, Ward D, Segal JB. JAMA.2013;309(12):1278-88.

AHRQ Grant HHSA 290 2007 10061

• Objective: Systematically review the effectiveness and safety of

aqueous SLIT for allergic rhinitis and asthma

• Methods: RCTs comparing SLIT to placebo, medication, or
• ther SLIT

– English language – Adult and Children – Similar formulation must be available in the U.S. – Must contain direct clinical outcomes

SLIT Aqueous SR Results

54

Literature Search

Medline, Embase, Lilacs, Cochrane

Search from database inception to Dec 2012

abstracts

8,156

Full article

1827

Final included

63 RCTs 5131 participants

55

• Age range 4-74
• Children only 20 studies (n=1814)
• Risk of Bias Moderate (68%)
• Comparator groups

– Placebo 73% – Other SLIT 14% – Meds 13%

SLIT Results

56

SLIT Results

Outcome

• No. Studies
• No. Participants

Strength of Evidence Asthma Symptoms 13 625 High Asthma Symptoms* 9 471 High

*Kim JM, Lin SY, Suarez-Cuervo C, Chelladurai Y, Ramanathan M, Segal JB, Erekosima N. Allergen-specific immunotherapy for pediatric asthma and rhinoconjunctivitis: a systematic review.Pediatrics. 2013 Jun;131(6):1155-67

57

• “The overall evidence provides a moderate grade level
• f evidence to support effectiveness of SLIT for AR and

asthma, but high-quality studies are still needed to answer questions regarding optimal dosing strategies. There were limitations in the standardization of adverse events reporting, but no life-threatening adverse events were noted in this review.” Systematic Review Conclusions

58

• 45 (75%) reported safety data
• Lack of standardized reporting
• Local reactions:

– SLIT 0.2-97% – Comparator 3-38.5%

• Systemic reactions rare
• No anaphylaxis or deaths

Lin SY, Erekosima N, Kim JM, Ramanathan M, Suarez-Cuervo C, Chelladurai Y, Ward D, Segal JB. JAMA.2013;309(12):1278-88.

SR: Safety Aqueous SLIT

59

SLIT Tablet Efficacy: United States Studies

60

SLIT Tablets: US Ragweed RCTs

Study N Age Dose Amb 1-U Duration Outcome Asthma Creticos P 2013 784 Adults 12 1 year 27% Asthma Sx Score, Entire Season (p=.022) Nolte HS 2013 565 Adults 12 1 year Not reported

61

SLIT Tablets: US Timothy RCTs

Study N Age Dose Micrograms Phl p 5 Duration Outcome: Asthma Blaiss M 2011 345 Children 5-17 15 Pre/co- seasonal 23 weeks No significant improvement well controlled and allowed asthma meds Nelson HS 2011 439 Adults 15 Pre/co- seasonal 23 weeks 24% TASS (p=.004)

62

SLIT Tablets: US Grass Mix RCTs

Study N Age Dose Duration Outcome: Asthma Wahn U 2009 278 Children 5-17 300IR Pre/co-seasonal Not reported Didier A 2011 633 Adults 300IR 4 mo pre/co- seasonal Not reported Cox LS 2012 473 Adults 300IR 4 mo pre/co- seasonal Not reported Didier A 2007 628 Adults 300IR 4 mo pre/co- seasonal Not reported

Effectiveness of Subcutaneous Versus Sublingual Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and Asthma: A Systematic Review

Yohalakshmi Chelladurai, MBBS, MPH, Catalina Suarez-Cuervo, MD, Nkiruka Erekosima, MD, MPH, Julia M. Kim, MD, MPH, Murugappan Ramanathan, MD, Jodi B. Segal, MD, MPH, and Sandra Y. Lin, MD J Allergy Clin Immunol Pract. 2013 Jul-Aug;1(4):361-9.

Which is more effective: SLIT vs SCIT?

• Systematic review of studies with head to head

comparison of SCIT and SLIT

• English language RCTs
• Results:

– 8 studies – 4 studies: allergic asthma outcomes – 6 studies: allergic rhinitis outcomes

SCIT vs SLIT SR

65

SLIT vs SCIT Results

Outcome No. Studies No. Participants Strength of Evidence Asthma 4 171 Low favoring subcutaneous Rhinoconjunctivitis 6 412 Moderate favoring subcutaneous Medication Use 5 219 Low minimal difference Combined Med Sx 2 65 Low favoring subcutaneous QOL 1 48 Insufficient

66

• Heterogeneous symptom scoring

– Sx-med scores primary outcome

• Lack of standardization for adverse event reporting

– WHO standards

• Lack of consistent statistical reporting
• Dosing units varied—how to translate?
• Comparison of US and European allergens

Studies– Challenges for Systematic Review

67

What are the knowledge gaps and challenges in SLIT facing US practitioners?

68

• Need for U.S. studies

Effectiveness of SLIT tablets for allergic asthma?

69

• Majority of SLIT efficacy studies done in Europe

– JAMA 7/63 studies N. America – Units not standardized around world

• Lack of Ag standardization: US vs. Europe

– Definitions & units vary – Translation to US dosing difficult

• Lack of large scale US studies

What dose should we give in the US for Aqueous SLIT?

Calderon MA, Simons FER, Malling HJ et al. Sublingual allergen immunotherapy: mode of action and its relationship with the safety profile. Allergy 2012; 67:302-311.

• JAMA 2013:

– Dust mite – Conversion to micrograms/month – Highest dose 50x greater than lowest effective dose What dose should we give in the US for Aqueous SLIT?

71

• Aqueous SLIT (Marogna 2010)

– DM 3, 4, 5 year – All lasting effects after d/c, up to 8 years – 4 years recommended as equivalent to 5

• Timothy SLIT Tab (Durham 2012)

– 3 yrs – 2 yr f/u continued effect

• Pre/coseasonal vs Year Round

– Need further follow up on pre/coseasonal

How long to treat?

72

• Europe-Single
• US-Multiple
• Most studies monotherapy
• Yet unanswered question as

inconsistent results To treat with single or multi-allergen SLIT?

73

• Elderly
• Pregnant women
• Minorities
• Inner-city and rural residents
• Patients with severe asthma

Is safety/effectiveness of immunotherapy different in distinct subpopulations?

74

• SLIT aqueous

– No CPT dosing – Limited publications on U.S. dosing

• SLIT tablets

– Limited number of allergens available

Other Concerns

75

KAS 11: Immunotherapy

SCIT SLIT

Effectiveness for allergic rhinitis Supported by systematic reviews of randomized, controlled trials Supported by systematic reviews of randomized, controlled trials Safety Deaths: 1 per 2.5 million injections No reported deaths Rate of systemic reactions 0.06%-0.9% 0.056% Dosing Administered in physician’s office Administered at home SLIT aqueous dosing not standardized First dose of SLIT tablet should be administered in physician’s office, epi autoinjector FDA status FDA approved SLIT aqueous FDA “off-label” use SLIT tablets approved by FDA in April 2014; limited number of allergens available for treatment Socioeconomic CPT code exists for SCIT vial preparation and injections Covered by most insurance plans No CPT code exists for SLIT aqueous

• preparation. SLIT aqueous not covered

by most insurance plans. SLIT tablet insurance coverage to be determined by individual insurance carriers.

• Moderate to high grade evidence supports use of both

SCIT and SLIT for allergic rhinitis and asthma.

• Low grade evidence supports SCIT more effective for

allergic asthma

• Clinical choice of therapy dependant on patient-

physician decision making Conclusions

77

Questions

Immunotherapy for the Treatment of Allergic Asthma: NIAID Research Programs Alkis Togias, MD

Branch Chief Allergy, Asthma, and Airway Biology Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases National Institutes of Health

• Long-term effects after therapy is discontinued
• Potential for asthma prevention
• Conduit to understand immune tolerance

– Fundamental immune alterations of “allergy” – Insights into other immune-mediated diseases (autoimmunity)

Allergen Immunotherapy: Reasons for NIAID’s Interest

• Efficacy well-demonstrated

However,

• Magnitude and duration of the clinical effect require

improvement

• Risks must be reduced
• Duration of treatment must be reduced
• Mechanism of action must be elucidated

Allergen Immunotherapy for Allergic Rhinitis and Asthma: Needs (A)

Goals and New Directions in Allergen Immunotherapy

Sublingual Epicutaneous

• Increase immunogenicity
• Decrease allergenicity
• Promote particular types of immune responses

Alternative routes of administration

Oral Intranodal Immunodominan t peptides

Alternative forms of allergen

Allergen modification Allergen “plus” Immunomodulators Adjuvants Chemical Molecular

• Questions raised by the AHRQ review

– SCIT vs SLIT – Mono vs multi-allergen therapy – Effects on disease progression (rhinitis to asthma) – Optimization of the dosing and duration of currently available forms of therapy

Allergen Immunotherapy for Allergic Rhinitis and Asthma: Needs (B)

• Biomarker development
• Development of immunotherapy for allergens

important to populations with increased morbidity Allergen Immunotherapy for Allergic Rhinitis and Asthma: Needs (C)

• Cockroach allergen immunotherapy program (Inner

City Asthma Consortium)

• Development of new forms of allergen

immunotherapy and investigations of the mechanisms of immune tolerance by allergen immunotherapy (Immune Tolerance Network)

• Individual grant support

NIAID Programs on Allergen Immunotherapy for Allergic Rhinitis and Asthma

The Importance of Cockroach Allergy in Inner-City Asthma

Asthma phenotyping

ICAC II 2009-2014 ICAC I 2002-2008

anti-IgE trial Stronger benefits in cockroach allergic and exposed

ICAS 1996-2001

Environmental Intervention Study Stronger benefits in cockroach allergic and exposed

NCICAS 1991-1995

Observational Study Cockroach allergy: Major risk factor for asthma morbidity

Probability of “Difficult-to-control” Allergen levels in house dust (µg/g)

The Importance of Cockroach Allergy in Inner- City Asthma

• Development of a successful german cockroach

immunotherapy regimen for the treatment (and prevention) of asthma and rhinitis in inner city populations

– Stepwise approach

• Step 1: extract evaluation
• Step 2: SLIT safety
• Step 3: SLIT and SCIT immunologic activity (3 studies)

Cockroach Allergen Immunotherapy Program

Cockroach Allergen Immunotherapy Program

Wood et al J Allergy Clin Immunol 2014;133:846

N=54 N=99 N=10

• Step 4: Efficacy evaluation of cockroach SCIT

– Study 1: Development of a nasal cockroach challenge model (10 adults followed by 25 children) – Study 2: Utilization of the nasal cockroach challenge as the primary outcome in a Phase IIa trial (children)

• 2 maintenance doses vs placebo
• 1 year duration
• Include secondary clinical outcomes of asthma and rhinitis
• Assess confounders (allergen exposure)

Cockroach Allergen Immunotherapy Program (ICAC 2015-2021)

• Development of a successful mouse immunotherapy

regimen for the treatment (and prevention) of asthma and rhinitis in inner city populations

– Study 1: SCIT safety and immunologic activity

Mouse Allergen Immunotherapy

• The ITN is focused on the development of therapeutic

approaches for asthma and allergy, autoimmune diseases, type 1 diabetes and solid organ transplantation that lead to immune tolerance

Immune Tolerance Network (ITN)

• Pioneering the concept of “allergen plus” where

allergen immunotherapy is delivered in combination with immunomodulators

– Anti-cytokine agents – T-cell depletion – Immune deviation – T-reg induction

• Modified allergens
• Alternative routes of allergen administration

Allergen Immunotherapy for Allergic Rhinitis and Asthma: ITN

Allergen Immunotherapy for Allergic Rhinitis and Asthma: ITN

Gauging the Response in Allergic rhinitis to Sublingual and Subcutaneous immunotherapy

GRASS Design

Year 1 assessment Random allocation Year 2 assessment Year 3 assessment Subcutaneous immunotherapy Sublingual immunotherapy Placebo (double dummy)

Oct 2011-Feb 2012 Start Rx

Jan 2013 Dec 2013 End Rx Jan 2015 Tolerance?

Baseline assessment

Mar-Sept

2011 Recruit/ screen

GRASS Design

Year 1 assessment Random allocation Year 2 assessment Year 3 assessment Subcutaneous immunotherapy Sublingual immunotherapy Placebo (double dummy)

Oct 2011-Feb 2012 Start Rx

Jan 2013 Dec 2013 End Rx Jan 2015 Tolerance?

Baseline assessment

Mar-Sept

2011 Recruit/ screen

GRASS Design

Year 1 assessment Random allocation Year 2 assessment Year 3 assessment Subcutaneous immunotherapy Sublingual immunotherapy Placebo (double dummy)

Oct 2011-Feb 2012 Start Rx

Jan 2013 Dec 2013 End Rx Jan 2015 Tolerance?

Baseline assessment

Mar-Sept

2011 Recruit/ screen

106 randomized, 92 completed the study

GRASS Design

2 sprays 100mcL each nostril 10-10,000 BU/ml Phleum Pratense

Nasal challenge device

GRASS Design

Sneezing 0-3 Nose running 0-3 Blockage 0-3 Itch 0-3 TOTAL 0-12

Modified from Bousquet et al 1987 and Lent et al 2006

Symptom score (TNSS) Peak nasal inspiratory flow

2 sprays 100mcL each nostril 10-10,000 BU/ml Phleum Pratense

Nasal challenge device

GRASS Results - Symptoms

On Treatment On Treatment Off Treatment

GRASS Results - Symptoms

SLIT- Placebo SCIT- Placebo SCIT- SLIT Year 1 14.7 34.0% 29.2% Year 2 27.0% 41.6% 25.1% Year 3

(off treatment)

5.6% 17.8% 14.9%

Treatment Percent Differences by Assessment Year

Shaded areas: p<0.05 comparing mean diameters adjusting for baseline year (ANCOVA)

GRASS Results – Nasal Airflow

On Treatment On Treatment Off Treatment

GRASS Results – Nasal Airflow

On Treatment On Treatment Off Treatment

GRASS Results – Nasal Airflow

On Treatment On Treatment Off Treatment

GRASS Results – Nasal Airflow

On Treatment On Treatment Off Treatment

SLIT versus SCIT

Efficacy ++ Safety + Efficacy + Safety ++ SCIT SLIT

Workgroup Participants’ Perspectives on Subcutaneous vs. Sublingual Immunotherapy for Allergic Asthma

Workgroup Participants’ Perspectives

Antonio Linares, MD Regional Vice President, Medical Director Anthem Blue Cross – Health and Wellness Solutions

108

Workgroup Participants’ Perspectives

Meryl Bloomrosen, MBI, MBA Senior Vice President Policy, Advocacy and Research Asthma and Allergy Foundation of America

109

Workgroup Participants’ Perspectives

Peter S. Creticos, MD Associate Professor of Medicine Division of Allergy and Clinical Immunology Johns Hopkins School of Medicine Director, Creticos Research Group

110

Workgroup Participants’ Perspectives

Lisa A. Gilmore, MBA, MSW Senior Consultant

111

Workgroup Participants’ Perspectives

Tyra Bryant-Stephens, MD Director and Founder, Community Asthma Prevention Program Children’s Hospital of Philadelphia Clinical Associate Professor of Pediatrics University of Pennsylvania School of Medicine Representing American Academy of Pediatrics

112

Workgroup Participants’ Perspectives

Bridget Smith, PhD Research Associate Professor, Pediatrics Northwestern University Feinberg School of Medicine

113

Workgroup Participants’ Perspectives

Jonca Bull, MD Assistant Commissioner for Minority Health U.S. Food and Drug Administration

114

Workgroup Participants’ Perspectives

Lynn Morrison President Washington Health Advocates Representing the American Academy of Allergy, Asthma and Immunology

115

Workgroup Participants’ Perspectives

Alkis Togias, MD Branch Chief, Allergy, Asthma and Airway Biology Division of Allergy, Immunology, and Transplantation National Institute of Allergy and Infectious Diseases National Institutes of Health

116

Workgroup Participants’ Perspectives

Kim Marie Wittenberg, MA Health Scientist Administrator Agency for Healthcare Research and Quality Center for Evidence and Practice Improvement

117

Lunch

• Visit us at www.pcori.org
• Submit comments via Chat

Workgroup Discussion: Components of Comparative Effectiveness Trial(s) for Subcutaneous vs. Sublingual Immunotherapy for Allergic Asthma

• Study design
• Active intervention and comparator(s)

– Allergen

• Restricted to FDA approved extract tablets?
• Other considerations: season variability, geography, populations

sensitized

– Dosing

• Population(s) and recruitment
• Cost and feasibility of trials

Discussion: Components of Comparative Effectiveness Trial(s) for Subcutaneous vs. Sublingual Immunotherapy for Allergic Asthma

Break

• Visit us at www.pcori.org
• Submit comments via Chat

Patient, System, and Community Factors for Conducting Trial on Subcutaneous vs. Sublingual Immunotherapy for Allergic Asthma

• Patient factors (e.g., engagement, education)
• Optimizing access (e.g., rural vs. urban)
• Clinical settings (e.g., PCP vs. specialty setting)
• Availability of information for PCPs and specialists
• Community involvement

Patient, System, and Community Factors for Conducting Trial on Subcutaneous vs. Sublingual Immunotherapy for Allergic Asthma

Discussion and Consensus around Key Research Gaps

Identification and Refinement of Comparative Effectiveness Research Questions

• Population
• Intervention
• Comparator
• Outcomes
• Time of observation
• Setting

How to describe a research question: PICOTS

PCORI Research Topic Criteria

• Patient-Centeredness: is the comparison relevant to patients, their caregivers,

clinicians or other key stakeholders and are the outcomes relevant to patients?

• Impact of the Condition on the Health of Individuals and Populations: Is the

condition or disease associated with a significant burden in the US population, in terms of disease prevalence, costs to society, loss of productivity or individual suffering?

• Assessment of Current Options: Does the topic reflect an important evidence gap

related to current options that is not being addressed by ongoing research.

• Likelihood of Implementation in Practice: Would new information generated by

research be likely to have an impact in practice? (E.g. do one or more major stakeholder groups endorse the question?)

• Durability of Information: Would new information on this topic remain current for

several years, or would it be rendered obsolete quickly by new technologies or subsequent studies?

Prioritized questions and deliberations from workgroup will be shared with PCORI leadership. Determination regarding funding announcements on specified topics made by PCORI Board of Governors by August 2015.

What happens next?

Thank You

Romana Hasnain-Wynia, PhD, MS

Program Director, Addressing Disparities

Contact Us

www.pcori.org info@pcori.org