emerging therapeutic options for asthma≤2 days/week >2 days/week but not daily daily throughout...

© 2011 Pharmacy Times Office of Continuing Professional Education (CPE).

Gene L. Colice, MDDirector, Pulmonary, Critical Care, and Respiratory Services

Washington Hospital CenterProfessor of Medicine

George Washington University

Improving Asthma Care: An Update for Managed CareEmerging Therapeutic Options

for Asthma


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Presenter:Gene L. Colice, MDDirector, Pulmonary, Critical Care, and Respiratory ServicesWashington Hospital CenterProfessor of MedicineGeorge Washington UniversityWashington, DC

Moderator:Jeff Prescott, PharmD, RPhDirector of Scientific ContentThe American Journal of Managed Care

This activity is supported by an educational grant from Merck & Co, Inc.

Faculty InformationFaculty Information


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Educational ObjectivesEducational ObjectivesAfter completing this activity, the participant should be able to:

Discuss the demographics, economics, and pathophysiology of asthmaDescribe the significance of unmet needs among people with asthma Examine new and emerging therapies for asthma and assess their role in the treatment of asthmaIdentify strategies for improving asthma control

The contents of this CE activity may include information regarding the use of products that may be inconsistent with or outside the approved labeling for these products in the United States. Physicians should note that the use of these products outside current approved labeling is considered experimental and are advised to consult prescribing information for these products.


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DisclosuresDisclosuresAccording to the disclosure policies of the University of Cincinnati and Pharmacy Times Office of Continuing Professional Education, faculty, editors, managers, and other individuals who are in a position to control content are required to disclose any relevant financial relationships with relevant commercial companies related to this activity. All relevant conflicts of interest that are identified are reviewed for potential conflicts of interest. If a conflict is identified, it is the responsibility of the University of Cincinnati and Pharmacy Times Office of Continuing Professional Education to initiate a mechanism to resolve the conflict(s). The existence of these interests or relationships is not viewed as implying bias or decreasing the value of the presentation. All educational materials are reviewed for fair balance, scientific objectivity of studies reported, and levels of evidence.

Gene L. Colice, MD reports consultancy, advisory board, and speaker’s bureau assignments from Abbott, Boehringer Ingelheim, Genentech, GlaxoSmithKline, MedImmune, Pearl Therapeutics, Pfizer, and Teva.

The planning staff from the University of Cincinnati, The American Journal of Managed Care, and the Pharmacy Times Office of Continuing Professional Education have no relevant financial relationships to disclose.


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Accreditation StatementThis activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the University of Cincinnati. The University of Cincinnati is accredited by theACCME to provide continuing medical education for physicians.

Credit DesignationThe University of Cincinnati designates this enduring material activity for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extentof their participation in the activity.

Physician AccreditationPhysician Accreditation


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Pharmacy Times Office of Continuing Professional Education is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This program is approved for 1 contact hour (0.1 CEU) under the ACPE universal program number 0290-9999-11-018-H01-P. This program is available for CE credit through April 19, 2012.

Type of Activity: Knowledge-based.

Pharmacy AccreditationPharmacy Accreditation


Emerging Therapeutic Options for Asthma

Send discussion questions to [email protected]


8Send discussion questions to [email protected]

What is the current state of asthma care?

How can we improve asthma care?

What are the new therapeutic options for asthma care and how effective are they?

Emerging Therapeutic Options for AsthmaEmerging Therapeutic Options for Asthma



Approximately 23.3 million Americans (2008 data)Affects all age groups◦ <5 yrs 1.28 million◦ 5-17 yrs 5.68 million◦ 18-44 yrs 7.94 million◦ 45-64 yrs 5.77 million◦ >65 yrs 2.65 million

American Lung Association. Trends in asthma morbidity and mortality: February 2010. http://www.lungusa.org.

Asthma DemographicsAsthma Demographics



Asthma DemographicsAsthma Demographics




Akinbami LJ, et al. Asthma prevalence, health care use, and mortality: United States, 2005-2009. National health statistics reports; No. 32. Hyattsville, MD: National Center for Health Statistics; 2011.

Utilization and Mortality from Asthma Utilization and Mortality from Asthma is Disparate (2005is Disparate (2005--2007)2007)

A rate ratio of 1.0 (dashed line) indicates equal rates between the groups being compared.

<18 years vs ≥18 years

Femalevs Male

Othervs White

Blackvs White

0.14

1.93

0.79

1.29

1.23

2.22

0.89

1.08

1.52

3.32

0.73

0.96

1.77

0.98

0.68

0.82

0 1 2 3 4

Total ambulatory visitEmergency department visitHospitalizationDeath



American Lung Association. Asthma in adults fact sheet. February 2010. CDC Summary Health Statistics for U.S. Adults: National Health Interview Survey, 2008. Series 10, Number 242; December 2009. CDC Summary Health Statistics for U.S. Children: National Health Interview Survey, 2008. Series 10, Number

244; December 2009. Akinbami LJ, et al. National health statistics reports; No. 32. Hyattsville, MD: National Center for Health Statistics; January 2011.

11--year Trends in Asthma, Utilization, year Trends in Asthma, Utilization, and Mortalityand Mortality

12.8 million with an attack

24.6 million with asthma

2009 Trend2008

12.7 million with an attack

23.4 million with asthma

3447 asthma deaths3613 asthma deaths

456,000 hospitalizations444,000 hospitalizations

1.75 million ED visits1.7 million ED visits

Trend20072006

ED = emergency department.



Asthma in America Survey, 1998:◦ 2 of 5 (39%) people with moderate persistent

asthma and >2 of 3 (68%) with severe persistent asthma did NOT consider their asthma to be “well controlled” or “completely controlled”

Asthma Insight and Management Survey, 2009: ◦ 42% of asthma patients were “poorly” or “not well

controlled”

Asthma in America™: A Landmark Survey. Executive Summary. SRBI, 2004.Murphy K et al. Ann Asthma Immunol. 2010;105(suppl 5):A50. Abstract P86.

Has the State of Asthma Care Changed Has the State of Asthma Care Changed in the Last 10 Years?in the Last 10 Years?



Direct medical costs◦ $5.5 billion – hospital care ◦ $5.9 billion – prescription care ◦ $4.2 billion – physicians’ services

Indirect medical costs◦ $3.1 billion – morbidity◦ $2.0 billion – mortality

Asthma EconomicsAsthma Economics




Mauad T et al. Abnormal Alveolar Attachments with Decreased Elastic Fiber Content in Distal Lung in Fatal Asthma. Am J Respir Crit Care Med. 2004;170(8):857-862.

Airway Inflammation in AsthmaAirway Inflammation in AsthmaSmall airway of acontrol subject

Small airway of asubject with fatal asthma

Airway inflammation is the underlying reason for asthma symptoms, airflow obstruction, exacerbations, and airway hyperresponsiveness.



Asthma Asthma PathophysiologyPathophysiology

National Asthma Education and Prevention Program, National Heart, Lung, and Blood Institute. Expert Panel report 3: guidelines for the diagnosis and management of asthma. Full report 2007.



Asthma Asthma PathophysiologyPathophysiology




Assessment of asthma should include:◦ Severity: the intrinsic intensity of the disease process ◦ Control: the degree to which the manifestations of asthma are

minimized and the goals of therapy are met◦ Responsiveness: the ease with which asthma control is achieved

by therapyAssessment of severity and control should include:◦ Impairment: frequency and intensity of symptoms and functional

limitations the patient is experiencing◦ Risk: the likelihood of either asthma exacerbations, progressive

decline in lung function (or, for children, reduced lung growth), or risk of adverse effects from medication

Expert Panel Report 3 (EPR3) Recommended Expert Panel Report 3 (EPR3) Recommended Approach to Asthma EvaluationApproach to Asthma Evaluation

National Asthma Education and Prevention Program, National Heart, Lung, and Blood Institute. Expert Panel Report 3: guidelines for the diagnosis and management of asthma. Full report 2007.



Assessing Severity Prior to Initiating Assessing Severity Prior to Initiating Controller MedicationController Medication

AssessingInitial

AsthmaSeverity

Impairment

Risk

Nighttime awakeningsShort-acting beta2-agonist (SABA) useSchool/work days missedInterference with normal activityQuality of lifeLung function (spirometry)

Previous oralcorticosteroid useFrequency and severity of recent symptoms indicative of persistent diseaseUrgent care visits




Classifying Asthma Severity in Patients Not Taking Classifying Asthma Severity in Patients Not Taking LongLong--term Controller Medication (Children 5term Controller Medication (Children 5--11 Years)11 Years)

EIB = exercise-induced bronchospasm; FVC = forced vital capacity.

Impairment

Symptoms

Nighttime awakenings

SABA use for symptom control (not prevention of EIB)

Interference with normal activity

Lung function

≤2 days/week >2 days/weekbut not daily Daily Throughout the

day

≤2x/month 3-4x/month >1x/week but not nightly

Often7x/week

≤2 days/week >2 days/weekbut not daily Daily Several times

per day

None Minor limitation Some limitation Extremely limited

Normal FEV1between exacerbationsFEV1 >80% predictedFEV1/FVC >85%

FEV1 ≥80% predicted

FEV1/FVC >80%

FEV1=60%-80% predicted

FEV1/FVC=75%-80%

FEV1 <60% predicted

FEV1/FVC <75%

RiskExacerbations requiring oral systemic corticosteroids

0-1/year ≥2/year

Consider severity and interval since last exacerbation. Frequency and severity may fluctuate over time for patients in any severity

category. Relative annual risk of exacerbations may be related to FEV1.

Components of SeverityIntermittent

(step 1)

PersistentMild

(step 2)Moderate(step 3)

Severe(step 3 or 4)




Asthma Treatment and ControlAsthma Treatment and Control




Once therapy has begun, the emphasis is on the assessment of asthma control

The level of asthma control will guide decisions either to maintain or adjust therapy

Asthma Treatment and ControlAsthma Treatment and Control




Assessing Control After Initiating Assessing Control After Initiating Controller MedicationController Medication

AssessingAsthmaControl

Impairment

Risk

Fewer daily symptomsFewer nighttime awakeningsLess frequent SABA useMaintain activity levelMaintain lung function

Not preventing exacerbationsand urgent care visitsPersistent airflow obstructionMedication-related adverse eventsNot providing optimal treatmentNot preventing lung function decline




Case Study #2: 32Case Study #2: 32--yearyear--old Male,old Male,Asthma Control Test (ACT) ScoreAsthma Control Test (ACT) Score

Scoring: ≤15 = poorly controlled; 16-19 = not well controlled, ≥20 = well controlled

Completely controlled

Well controlled

Somewhat controlled

Poorly controlled

Not controlled at all

5. How would you rate your asthma control during the past 4 weeks?

Not at allOnce a week or less

2 or 3 times per week

1 or 2 times per day

3 or more times per day

4. During the past 4 weeks, how often have you used your rescue inhaler or nebulizer medication (such as albuterol)?

Not at allOnce or twiceOnce a week2 or 3 nights

a week4 or more

nights a week

3. During the past 4 weeks, how often did your asthma symptoms (wheezing, coughing, shortness of breath, chest tightness, or pain) wake you up at night, or earlier than usual in the morning?

Not at allOnce or twice a week

3 to 6 times a weekOnce a dayMore than once

a day

2. During the past 4 weeks, how often have you had shortness of breath?

None of the time

A little of the time

Some of the time

Most of thetime

All of the time

1. In the past 4 weeks, how much of the time did your asthma keep you from getting as much done at work, at school, or at home? Score

1 2 3 4 5

1 2 3 4 5

1 2 3 4 5

1 2 3 4 5

1 2 3 4 5

5

4

5

4

4

22Score



Assessing Asthma Control in Individuals Assessing Asthma Control in Individuals ≥≥12 Years of Age12 Years of Age

Components of Control Well Controlled Not Well Controlled Very Poorly Controlled

Impairment

Symptoms ≤2 days/week >2 days/week Throughout the day

Nighttime awakenings ≤2x/month 1-3x/week ≥4x/week

SABA use for symptom control (not prevention of EIB)

≤2 days/week >2 days/week Several times per day

Interference with normal activity None Some limitation Extremely limited

FEV1 or peak flow >80% predicted/personal best

60%-80% predicted/personal best

<60% predicted/personal best

Validated questionnairesATAQACQACT

0≤0.75≥20

1-2≥1.5

16-19

3-4N/A≤15

Risk

Exacerbations requiring oral systemic corticosteroids

0-1 per year ≥2 per year

Consider severity and interval since last exacerbation.

Progressive loss of lung function Evaluation requires long-term follow-up care.

Treatment-related adverse effects

Medication side effects can vary in intensity from none to very troublesome and worrisome. The level of intensity does not correlate to specific levels of control but should be considered in overall assessment of risk.




Stepwise Approach for Managing Asthma Stepwise Approach for Managing Asthma in Individuals in Individuals ≥≥12 Years Old12 Years Old

IntermittentAsthma

Persistent Asthma: Daily MedicationConsult with asthma specialist if step 4 care or higher is required.

Consider consultation at step 3.

STEP 1

PREFERRED

SABA prn

STEP 2

PREFERRED

Low-dose ICS

Alternative:Cromolyn,

LTRA, nedocromil, or theophylline

STEP 3

PREFERRED

Low-dose ICS+ LABA

ORMedium-dose

ICS

Alternative:Low-dose ICS

+ LTRA, theophylline, or zileuton

Quick-relief medication for all patients:• SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms: up to 3 treatments at 20-

minute intervals as needed. Short course of systemic oral corticosteroids may be needed.• Use of SABA >2 days/week for symptom relief indicates inadequate control and the need to step up treatment.

STEP 4

PREFERRED

Medium-dose ICS + LABA

Alternative:Medium-dose ICS + LTRA, theophylline, or zileuton

STEP 5

PREFERRED

High-dose ICS + LABA

AND

Consider omalizumabfor patients who have allergies

STEP 6

PREFERRED

High-dose ICS + LABA + oral

systemic corticosteroid

AND

Consider omalizumab for

patients who have allergies

Each step: Patient education, environmental control, and management of comorbidities.Steps 2-4: Consider subcutaneous allergen immunotherapy for patients who have allergic asthma.

Step up if needed(first, check adherence,

environmental control, and comorbid

conditions)

Step down if possible

(and asthma is well controlled at least 3 months)

ASSESS CONTROL




The goal of treatment is to achieve asthma control

Unfortunately, not all patients achieve that goal

Asthma Treatment and Control?Asthma Treatment and Control?




Bateman ED, Boushey HA, Bousquet J, et al. Can guidelines-defined asthma control be achieved? the gaining optimal asthma control study. Am J Respir Crit Care Med. 2004;170(8):836-844.




“Asthma is an inflammatory disorder of the airways that affects approximately 300 million people worldwide. A significant number of these patients, estimated at 10% to 15%, have severe disease that is mechanistically heterogeneous and poorly controlled by conventional therapy.”

Bhat KD, Calhoun WJ. Omalizumab in asthma: is the therapeutic window too small? Chest. 2011;139(1):8-10.




Novel ICS combinationsCytokine inhibitorsPDE inhibitorsOligonucleotidesNon-pharmacologic options

Emerging Treatment OptionsEmerging Treatment Options



ICS plus leukotriene receptor antagonist (LTRA)ICS plus anticholinergicICS plus omalizumab

Novel ICS CombinationsNovel ICS Combinations



MONICA studyAdult patients (n = 1681) with mild to moderate asthma Montelukast 10 mg added to ICS or ICS + LABAFollowed for 6 months in a prospective, open-label observational study Primary end point: change in ACT score Secondary end points: mini-AQLQ and FEV1/PEF

Virchow JC, Mehta A, Ljungblad L, Mitfessel H; MONICA study group. Add-on montelukast in inadequately controlled asthma patients in a 6-month open-label study: the MONtelukast In Chronic Asthma (MONICA) study. Respir Med. 2010;104(5):644-651.

ICS Plus LTRAICS Plus LTRA



ICS Plus LTRAICS Plus LTRA

Virchow JC, Mehta A, Ljungblad L, Mitfessel H; MONICA study group. Add-on montelukast in inadequately controlled asthma patients in a 6-month open-label study: the MONtelukast In Chronic Asthma (MONICA) study. Respir Med. 2010;104(5):644-651.



Omalizumab is recommended for patients with severe uncontrolled asthma on ICS or ICS plus LABA (step 5 or 6)

ICS Plus ICS Plus OmalizumabOmalizumab




Busse W, Corren J, Lanier BQ, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol. 2001;108(2):184-190.




Rodrigo FJ, Neffen H, Castro-Rodriguez JA. Efficacy and safety of subcutaneous omalizumab vs placebo as add-on therapy to corticosteroids for children and adults with asthma: a systemic review. Chest. 2011;139(1):28-35.

Rodrigo et al (2011) analyzed data from 8 RCTs and concluded that the addition of omalizumab◦ Reduced

Asthma exacerbations (37 exacerbations / 100 patient yrs vs69.9 exacerbations / 100 patient yrs – placebo) (primary outcome)Rescue medication use (secondary outcome)Asthma symptom scores (secondary outcome)

◦ IncreasedPercentage of patients able to stop their corticosteroid use completely (41.8% vs 21% – placebo) (primary outcome)Pulmonary function (FEV1 or PEF) (secondary outcome)Morning PEF (secondary outcome)Quality of life (AQLQ) scores (secondary outcome)




TALC study (Tiotropium Alternative to Low dose Corticosteroid study)Tiotropium approved for COPD, not asthmaAdult patients (n = 210) with poorly controlled asthma on ICSThree-way, double-blind, triple-dummy crossover trial1. Doubling dose of ICS (beclomethasone 160 μg twice daily),2. Normal dose ICS (beclomethasone 80 μg twice daily) plus the LABA

salmeterol xinafoate (50 μg twice daily), or 3. Normal dose ICS (beclomethasone 80 μg twice daily) plus tiotropium

bromide (18 μg each morning)

Peters SP, Kunselman SJ, Icitovic N, et al. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med. 2010;363(18):1715-1726.

ICS Plus ICS Plus AnticholinergicAnticholinergic



Primary end point – morning PEFSecondary end points – evening PEF, FEV1, various asthma and QoL scores





Long AA. Monoclonal antibodies and other biologic agents in the treatment of asthma. MAbs. 2009;1(3):237-246.

Numerous targetedstrategies studied. The most promising are:• IL-5 antagonist

(mepolizumab)• IL-2α receptor antagonist

(daclizumab)• TNF antagonists

(etanercept, infliximab)

Cytokine InhibitorsCytokine Inhibitors



Flood-Page P, Swenson C, Faiferman I, et al. A study to evaluate safety and efficacy of mepolizumabin patients with moderate persistent asthma. Am J Respir Crit Care Med 2007;176(11):1062-1071.

Mepolizumab◦ A humanized monoclonal antibody against interleukin-5◦ IL-5 is believed to be a key cytokine in eosinophil

differentiation, recruitment, activation, and survival at sites of allergic inflammation◦ Initial RCTs were not positive (eg, Flood-Page et al 2007)◦ Recent studies focusing on patients with eosinophilic

asthma show promise

Cytokine Inhibitors: Cytokine Inhibitors: MepolizumabMepolizumab



Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. New Engl J Med. 2009;360(10):973-984.

Haldar et al (2009) performed a randomized, double-blind, placebo-controlled, parallel-group study of patients (n = 61) with refractory eosinophilic asthma and a history of recurrent severe exacerbations Patients received 12 monthly infusions of mepolizumab(750 mg; n = 29) or placebo (n = 32) At the end of the 50-week study, the patients treated with mepolizumab had ◦ Fewer severe exacerbations (2.0 vs 3.4 mean exacerbations per

patient; relative risk, 0.57; 95% CICI, 0.32 to 0.92; P = .02)◦ Higher increase in AQLQ (mean increase from baseline, 0.55 vs

0.19; mean difference between groups, 0.35; 95% CI, 0.08 to 0.62; P = .02)

Cytokine Inhibitors: Cytokine Inhibitors: MepolizumabMepolizumab



Busse WW, Israel E, Nelson HS, et al. Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a randomized, controlled trial. Am J Respir Crit Care Med. 2008;178(10):1002-1008.

Daclizumab◦ A monoclonal antibody that binds to the receptor for IL-2

and inhibits the biological activity of IL-2◦ Busse et al (2008) performed a randomized, double-

blinded, placebo-controlled study in adults with moderate-to-severe persistent asthma given daclizumab (intravenous loading dose, 2 mg/kg, then 1 mg/kg; n = 88) or placebo (n = 27) every 2 weeks while also being tapered off of an ICS

Cytokine Inhibitors: Cytokine Inhibitors: DaclizumabDaclizumab



During the first 12 weeks of the study, ◦ Daclizumab improved FEV1 (daclizumab, 4.4 % vs

placebo, 1.5 %; P = .05), and reduced daytime asthma symptoms (P = .018) and short-acting inhaled beta2-agonist use (P = .009)◦ Daclizumab treatment prolonged time to exacerbation

(P = .024)During the final 24 weeks of study,◦ Significant differences in outcomes were not observed

between the 2 groups once the ICS dose was tapered off





Medications that can interfere with tumor necrosis factor (TNF) have also been investigated. Among them, the TNF antagonist etanercept shows some promise Two clinical studies have examined the efficacy of etanercept in patients with asthma

Cytokine Inhibitors: Cytokine Inhibitors: EtanerceptEtanercept



Berry MA, Hargadon B, Shelley M, et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med. 2006;354(7):697-708.

Berry et al (2006) conducted a small crossover study (n = 10) in patients with mild-to-moderate refractory asthmaPatients given etanercept (25 mg twice weekly for 10 weeks) had: ◦ Significant increase in the concentration of

methacholine required for 20% decrease in FEV1◦ Increase in post-bronchodilator FEV1◦ Higher AQLQ scores




Morjaria JB, Chauhan AJ, Babu KS, Polosa R, Davies DE, Holgate ST. The role of a soluble TNFalpha receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial. Thorax. 2008;63(7):584-591.

Morjaria et al (2008) conducted a randomized, double blind, placebo-controlled, parallel group trial Etanercept (50 mg, once weekly for 12 weeks) vsplacebo in 39 patients with severe corticosteroid refractory asthmaResults◦ Decrease in Asthma Control Questionnaire (ACQ) scores were:

Etanercept; -1.11 (95% CI -1.56 to -0.75) and Placebo; -0.52 (95% CI -0.97 to -0.07), P = .037

◦ No significant differences in Asthma Related Quality of Life (AQLQ)Peak expiratory flow (PEF)Bronchial hyperresponsiveness (BHR)




Erin EM, Leaker BR, Nicholson GC, et al. The effects of a monoclonal antibody directed against tumor necrosis factor-alpha in asthma. Am J Respir Crit Care Med. 2006;174(7):753-762.

Another TNF antagonistErin et al (2006) conducted a double-blind, placebo-controlled, parallel-group design study comparing infliximab (5 mg/kg iv at weeks 0, 2, and 6) with placebo in 38 patients with moderate asthma treated with ICS but symptomatic during a run-in phase At the end of the study, no significant difference in the primary end point was observed (morning PEF at end of study compared with end of run-in period) But the infliximab group had significantly fewer patients with exacerbations compared with placebo (29% vs72%)

Cytokine Inhibitors: Cytokine Inhibitors: InfliximabInfliximab



Bateman ED, Izquierdo JL, Harnest U, et al. Efficacy and safety of roflumilast in the treatment of asthma. Ann Allergy Asthma Immunol. 2006;96(5):679-686.

Phosphodiesterase type 4 (PDE4) is expressed in inflammatory cells involved in the pathogenesis of asthmaInhibition of PDE4 activity prevents the breakdown of cAMP, resulting in down-regulation of the inflammatory processes in cells involved in the pathogenesis of asthmaRoflumilast used in Europe for COPD; approved in March 2011 by FDA for severe COPD

PDE InhibitorsPDE Inhibitors



Bousquet J, Aubier M, Sastre J, et al. Comparison of roflumilast, an oral anti-inflammatory, with beclomethasone dipropionate (BDP) in the treatment of persistent asthma. Allergy. 2006;61(1):72-78.

Bousquet et al (2006) compared roflumilast (500 μgonce daily) with inhaled beclomethasonedipropionate (200 μg twice daily) in a double blind, double-dummy, randomized, noninferiority study involving patients with persistent asthma (N = 499)At the end of the 12-week study, both medications significantly improved FEV1 (roflumilast 12% increase; BDP, 14% increase) and forced vital capacity (roflumilast, 270 ml increase; BDP, 330 ml increase)





Bousquet J, Aubier M, Sastre J, et al. Comparison of roflumilast, an oral anti-inflammatory, with beclomethasone dipropionate (BDP) in the treatment of persistent asthma. Allergy. 2006;61(1):72-78.



Oligonucleotides can target RNA or proteins to alter cellular signalingAdvantages◦ High degree of specificity◦ Broad range of potential targets◦ Easy to modify drug properties ◦ Ability to screen efficiently for off-target effects◦ Relatively short development time◦ Relative ease of formulation for inhaled delivery◦ Relative ease of formulation of combination drugs◦ Relative stability of drug compound

Parry-Billings M, Ferrar N, Sequin R. Oligonucleotides: new therapeutic approaches for asthma and chronic obstructive pulmonary disease. Current Opin Invest Drugs. 2010;11(11):1276-1285.

OligonucleotidesOligonucleotides



Drug Type Drug Target StatusAntisense ASM-8 (Pharmaxis) CCR3 receptor and β-

chain of IL-3, IL-5, and GM-CSF receptors

Phase II

siRNA Excellair (ZaBeCorPharmaceutical)

Syk kinase Phase II

Immuno-stimulatory

CYT-003 (CytosBiotechnology)

TLR9 Phase II

Immuno-stimulatory

QAX-935 (IderaPharmaceuticals)

TLR9 Phase I

OligonucleotidesOligonucleotides



ASM-8 has 2 modified phosphorothioate antisense oligonucleotides that target CCR3 as well as the beta chain of IL-3, IL-5, and GM-CSFGauvreau et al (2008) performed a phase 2, crossover study in 17 patients with mild atopic asthma who were randomized to inhale 1500 μg TPI ASM8 or placebo by nebulizer, once daily for 4 daysAn allergen inhalation challenge on day 3Results:◦ Compared with placebo, TPI ASM8 inhibited sputum

eosinophil influx by 46% (P = .02) and blunted the increase in total cells (63%) after allergen challenge

Gauvreau GM, Boulet LP, Cockcroft DW, et al. Antisense therapy against CCR3 and the common beta chain attenuates allergen-induced eosinophilic responses. Am J Respir Crit Care Med. 2008;177(9):952-958.

OligonucleotidesOligonucleotides: ASM: ASM--8 (TPI8 (TPI--ASMASM--8)8)



CYT003-QbG10 is an immunostimulatory sequence drug encapsulated in a virus-like particleA phase 2 trial has been completedData unavailable but a press release noted that patients stabilized on ICSs were given CYT003-QbG10 or placebo as their dose of ICS was gradually reducedResults:◦ At the end of the 12-week study, average asthma symptom

score increased 29% in patients given placebo and decreased 33% in patients given CYT003-QbG10 (P = .01)

Cytos Biotechnology: Placebo controlled phase II study shows CYT003-QbG10 is safe and efficacious for the treatment of allergic asthma. Press Release (May 2010). www.cytos.com.

OligonucleotidesOligonucleotides: CYT003: CYT003--ObG10ObG10



Bronchial thermoplasty◦ Heat is applied to the bronchus by bronchoscopyCastro et al (2010) randomized 288 patients with uncontrolled severe asthma (on ICS and LABA) to receive bronchial thermoplasty or sham during 3 bronchoscopy procedures scheduled 3 weeks apart

Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med. 2010;181(2):116-124.

NonpharmacologicNonpharmacologic OptionsOptions




Castro M. Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med. 2010;181(2):116-124.



What is the current state of asthma care?

How can we improve asthma care?

What are the new therapeutic options for asthma care and how effective are they?

Emerging Therapeutic Options Emerging Therapeutic Options for Asthmafor Asthma



Improvement in our understanding of asthma pathophysiology and the development of novel therapies have created new options for patients with asthma who are not responding well to traditional treatments

More clinical trials are needed, but the future is promising for patients with asthma, including those with hard-to-treat, persistent asthma

ConclusionsConclusions


62

THANK YOU!

For any questions regarding this activity, contact: [email protected]

Emerging Therapeutic Options Emerging Therapeutic Options for Asthmafor Asthma

emerging therapeutic options for asthma≤2 days/week >2 days/week but not daily daily throughout...

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