Getting Beyond Prevention Inventive Strategies for...
Transcript of Getting Beyond Prevention Inventive Strategies for...
Getting Beyond Prevention
Inventive Strategies for COPDTim Joslin
Managing Director, Europe
Defined HealthWebinar 17th June, 2009
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The information in this presentation has been obtained from what are believed to be reliable sources and has been verified whenever possible. Nevertheless, we cannot guarantee the information contained herein as to accuracy or completeness. All expressions of opinion are the responsibility of Defined Health, and though current as of the date of this report, are subject to change.
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Defined Health is a leading business development strategy consulting firm. We have been assisting clients in the pharmaceutical, biotech and healthcare investment industries for more than 25 years. Our services, broadly described along with typical questions from our clients, include:
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Defined Health Areas of Experience and Expertise
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Defined Health Areas of Experience and Expertise
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Respiratory Disease: Experience & Expertise
♦ RESPIRATORY DISEASE is an active area of research for Defined Health, and includes extensive assessments in both the Allergist and Pulmonologist side of these disorders (as well as their overlap into the PCP space).
♦ Defined Health has recently conducted a very large review of the COPD current and future management landscape, including a very granular analysis of novel MOAs.
♦ Defined Health has conducted numerous commercial evaluations of novel MOAs such as FLAP and CRTH2 inhibitors, interleukin antagonists, and historically did many analyses around leukotriene modifiers and PDE-IV inhibitors.
♦ Because of Defined Health’s extensive client base of drug delivery companies, we have extensive experience looking at novel inhalation and intranasal platforms, both for next generation agents, novel agents, as well as lower risk branded generics, for asthma, allergic rhinitis, and COPD.
♦ Finally, Defined Health has conducted assessments of smaller, niche and orphan settings such as Idiopathic Pulmonary Fibrosis (IPF) and Cystic Fibrosis (CF).
Respiratory Disease
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AgendaCOPD impact – epidemiology, healthcare costs, ‘unseen’ patients, risk factorsCurrent therapiesUnderlying immunological mechanismsRegulatory & clinical trial IssuesFuture approaches to therapy
Still unproven routes of development■ PDE-4’s■ Anti-TNFα’s ■ IL8 Old drugs, new strategies■ Antibacterial therapy■ HDAC■ StatinsPotential ways forward?■ Leukotriene antagonists■ PI3K
Conclusion
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Definition of COPD
“COPD is a preventable and treatable disease with some significant extra-pulmonary effects that may contribute to the severity in individual patients. Its pulmonary component is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung tonoxious particles or gases.”GOLD, ATS/ERS spirometric classification based on post-bronchodilator FEV1
■ Stage 1 (FEV1 ≥80% predicted)■ Stage 2 (FEV1 <80% predicted)■ Stage 3 (FEV1 <50% predicted)■ Stage 4 (FEV1 <30% predicted)
COPD prevalence estimates are based on the sum of individual patients with either Chronic Bronchitis or Emphysema or a diagnosis of both conditions.
GOLD executive summary Am J Respir Crit Care Med 2007
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COPD is a Constellation of Overlapping Disorders
In 1989, Snider et al published a non-proportional Venn diagram illustrating the idea that COPD encompasses a group of disorderscharacterized by the presence of incompletely reversible airflowobstruction with overlapping subsets of different phenotypes including chronic bronchitis, emphysema or asthma.
Am Rev Respir Dis 1989;140(3 Pt 2):S3–8; Thorax 2008;63;761-767
In 2008, Marsh et al attempted to quantify the proportional classifications of Snider’s original COPD phenotypes. Based on spirometry and the overlap of three respiratory disorders, there are at least 8 distinct phenotypic subgroups of COPD. KOLs consistently pointed out that one wouldn’t expect a single drug to work on all of these subgroups.
The implications of inadequate patient/disease categorization are multifold:Patients are not well managed by physicians as COPD is a complex disease.Epidemiology of patients defined as having COPD is not accurate.Drugs targeting modulation of underlying pathophysiology may not work across broad populations.
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Risk Factors for COPDInhalation exposure■ Cigarette smoking -- 15-20% smokers develop clinically significant COPD■ Occupational dusts and chemicals■ Indoor/outdoor pollution
Genetic disposition■ Severe hereditary deficiency of α1-antitrypsin
Gender■ Equal prevalence in men and women – higher smoking prevalence in
women?Infection■ History of severe childhood infections■ Susceptibility to viral infections (due to low birth weight)
Socioeconomic status■ Risk of developing COPD inversely proportional to socioeconomic status
– probably due to a combination of exposures to pollutants, cigarette smoke, poor nutritional status
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COPD Co-morbidities Include…(Gold Stage 3, 4 patients) a higher prevalence of Coronary Heart Disease, diabetes and hypertension than age/sex/smoking status matched subjects.
As well as Depression, Muscle wasting and Cachexia.
What does this mean for companies looking to enter the space?
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High Burden of COPD in U.S.COPD is the 4th leading cause of morbidity and mortality in US after CVD, cancer, Cerebrovascular disease. Predicted to become 5th major worldwide burden of disease by 2020.2006 epidemiological estimates show 12.1M US citizens (over 18 years) having been diagnosed with COPD – sum of estimated cases of emphysema (4.1M) and chronic bronchitis (9.5M)The true prevalence of persons with reduced lung function maybe as much as double this figure■ NHANES III included spirometry on 82% of the 20,050 nationally
representative sample -- COPD prevalence estimated at 23.6M■ NHANES III cohort -- majority with mild/moderate disease as only 2.4M
with Gold Stage 3, 4■ 63% of adults identified with impaired airflow were unaware of their
condition■ Lung Health Study demonstrated patients who abstained from smoking
for at least 5 years have significantly improved survivalThe annual cost of treating US COPD patients in 2007 was $42.6 Billion –inclusive of $26.7 Billion in direct healthcare expenditures
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Even with Explosive Epidemiology, Diabetes Represents < 15 Million ‘Diagnosed’ Cases in 2005
US Dept HHS
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High but Variable COPD Mortality by Country
A ‘typically’ British
Disease?
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Current Management
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Management Algorithm for Mild COPD
International Journal of COPD 2008:3(4) 563–573
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COPD Market Value – Major ClassesDriven by SpirivaChange to ICS/LABA
Combination Therapy
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Current Management - Devices
COPD is a multi-billion dollar market defined by pulmonary inhalation devices delivering agents that provide only symptomatic relief.
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Treatment Effects
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Outcomes StudiesSpiriva’s position is enhanced by UPLIFT study results
UPLIFT was a 4 year trial sponsored by Boehringer Ingelheim with nearly 6000 patients that tested Spiriva vs. placebo. therapy with tiotropium was associated with improvements in lung function, quality of life, and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV1.
“Tiotropium was associated with a significant delay in the time to the first exacerbation, with a median of 16.7 months (95% CI, 14.9 to 17.9) in the tiotropium group and 12.5 months (95% CI, 11.5 to 13.8) in the placebo group. Tiotropium was also associated with a significant delay in the time to the first hospitalization for an exacerbation.”
N Engl J Med 2008;359:1543-54.
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Outcomes Studies
INSPIRE Shows Some Benefits of Advair• INSPIRE only showed Advair to be non-inferior to Spiriva in terms of preventing acute exacerbations.
Since UPLIFT was Spiriva vs. placebo, INSPIRE for GSK should help to nullify any advantage Boehringer Ingelheim may have received from UPLIFT.
♦ INSPIRE compared Advair and Spiriva in about 800 patients over 2 years. The primary endpoint was health care utilization exacerbation rate, defined as those that required treatment with oral corticosteroids and/or antibiotics or required hospitalization.
♦ The estimated overall rates of exacerbations were 1.28 per year for Advair and 1.32 per year for Spiriva, with no statistically significant difference.
Am J Respir Crit Care Med Vol 177. pp 19–26, 2008
♦ Secondary endpoints favored Advair, including statistically significant differences in the St. George’s Respiratory Questionnaire, a survey instrument designed to assess total patient health, and, surprisingly, mortality (3% vs. 6%).
♦ More cases of pneumonia occurred in the Advair-treated patients. Recent findings from other researchers have indicated that inhaled steroids reversibly increase the risk of pneumonia in COPD patients.
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Standard Bronchodilator/ICS Regimens May Decrease the Rate of Lung Function Decline…..but not Enough
Reducing the rate of lung function decline in COPD remains a high-priority. Long-acting bronchodilators may help in this regard (confirmatory studies are needed), but are unable reduce rates to those observed with healthy subjects. Indeed, their effects on lung function decline may be limited by a therapeutic ceiling. Thus, novel approaches may be needed to achieve the next incremental reduction in the rate of lung function decline.
International Journal of COPD 2009:4 185–201
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Bronchodilator/ICS Regimens Can Reduce the Burden of COPD Exacerbations…..but not Enough
International Journal of COPD 2009:4 185–201
COPD exacerbations are associated with increase mortality and morbidity. They also represent a major driver of disease-related costs. Thus, they are prime targets for pharmacological intervention.
LABAs, LAMAs, and ICSs have been shown to reduce the frequency, duration, and intensity of exacerbations. And data from the UPLIFT study suggest that triple combination therapy may be warranted. However, the overall burden associated with COPD exacerbations remains high.
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Benefits of Smoking Cessation
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Other Factors Apart from Smoking Clearly Contribute to COPD
Center on an Aging Society analysis of data from the 1998 National Health Interview Survey.
“We seem to have become fixated with this simple paradigm that smoking causes inflammation causes airflow obstruction causes COPD, and that is not right. COPD is a number of different diseases, so we need to have research into the different paradigms. If you’re looking at emphysema, for example, the treatment for emphysema will be very different from the treatment for COPD and chronic bronchitis, so I would encourage people to try and break the COPD mold and look at the subsets within that blanket definition. It served its purpose very well, but it’s now time to move beyond that.” – Pulmonologist
“We seem to have become fixated with this simple paradigm that smoking causes inflammation causes airflow obstruction causes COPD, and that is not right. COPD is a number of different diseases, so we need to have research into the different paradigms. If you’re looking at emphysema, for example, the treatment for emphysema will be very different from the treatment for COPD and chronic bronchitis, so I would encourage people to try and break the COPD mold and look at the subsets within that blanket definition. It served its purpose very well, but it’s now time to move beyond that.” – Pulmonologist
30%
31%39%
COPD Patients
Non-smoker
Current Smoker
Former Smoker
• The heterogeneity of COPD is underscored by the fact that smoking is a key precipitating factor but that the disease requires a complex interplay of extrinsic as well as intrinsic factors specific to a given person.
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Underlying Immunological Mechanisms
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Asthma COPD
Barnes PJ, Nature Reviews immunology vol 8, March 2008
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Similar Patterns of Inflammation in COPD & Severe Asthma• The historical paradigm of developing symptomatic relief drugs for asthma and then
expanding into COPD will become increasingly difficult in the coming years. • Due to the genericization of the symptom relief market and drugs developed to address
the pathophysiology of asthma may not be as effective in COPD as the cell types & mechanisms appear for the most part distinct between asthma and COPD. However, there are clearly points of intersection such as IL-13 and p38.
Barnes PJ, Nature Reviews immunology vol 8, March 2008
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Current and Future Medical Needs
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Current & Future Medical Needs
Effective implementation of early smoking cessation education & treatment
Easy to use devices and/or oral approaches to therapy
Screening of patients with risk factors for COPD
Earlier diagnosis of the disease – not when symptoms are severe enough for patient to present to PCP
Biomarkers to identify early disease and progression
Finding disease modifying approaches
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Regulatory & Trial Issues
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Lung Function
Other standards help to define respiratory failure, hyperinflation and dyspnea:■ Arterial Oxygen Tension (PaO2) and
Arterial Carbon Dioxide Tension (useful outcomes in interventional studies that affect lung ventilation perfusion relationships)
■ Lung Volume at rest or exercise (measured by more complicated equipment than spirometers)
It has also been suggested that inspiratory capacity be used in the clinic in order to monitor hyperinflation changes which cannot be detected by spirometry
FEV1 is the FDA accepted gold standard for diagnosis and staging■ Spirometry is the measuring tool for FEV1
■ Currently the only accepted primary endpoint for efficacy of pharmacological development
Cazzola M. et al. Outcomes for COPD pharmacological trials: from lung function to biomarkers Eur Respir J 2008
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Exacerbation Frequency and SeverityDefinition
■ Four types of exacerbation are defined in the literature
■ All types of exacerbations include any increase in respiratory symptoms over baseline
■ A majority of patients are aware that an exacerbation is imminent and symptoms tend to be consistent from one to another
Clinical trial significance
■ Trials using exacerbation frequency tend to be longer than a year because seasonal variation (environmental) factors into the frequency of events
■ However patient population is skewed toward patients that have 0-2 exacerbations a year as opposed to 10 or more
■ Frequency and severity of these events tend to be monitored with patient diaries
■ There are currently no biomarkers to measure risk or severity of exacerbation
Cazzola M. et al. Outcomes for COPD pharmacological trials: from lung function to biomarkers Eur Respir J 2008
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MortalityTo date mortality is the most robust clinical outcome in COPD researchAll-cause mortality is used because most patients do not die from COPD, but instead a complication of the diseaseHowever all other variables aside from FEV1 and Body Mass Index, Obstruction, Dyspnea, and Exercise endurance Index (BODE Index) have shown to be poor surrogates for predicting mortality
Cazzola M. et al. Outcomes for COPD pharmacological trials: from lung function to biomarkers Eur Respir J 2008
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Other MeasuresQuality of Life measure (QoL)
■ Poor correlation between FEV1 scores and QoL ratings
■ Clinical trials tend to include QOL as a secondary endpoint in conjunction with FEV1 scores
Exercise Tolerance
■ Differences in physiological response to these tests can show improvement in dyspnea and arterial oxygen saturation
■ The 6 Minute Walk Test (6MWT) is a widely used as a secondary outcome measure to show benefits of pharmacological intervention
Imaging
■ Imaging is a hotly debated issue amongst clinicians over the past year
■ The main problem of imaging for small airways in COPD patients is the lack of a validated methodology for performing the procedure and collecting the data
■ Although it may show promise in detection of airway remodeling, it is a long way of from an acceptable trial endpoint
Cazzola M. et al. Outcomes for COPD pharmacological trials: from lung function to biomarkers Eur Respir J 2008
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FDA Guidance for Development
Drug effectImprove Airflow
Obstruction
Symptom Relief
Modify exacerbations
Alter Disease Progression
Modify Lung Structure
Primary Endpoint
Immediate change in FEV1
Reflect claimed clinical benefit
Duration, severity, delay, and frequency should all be assessed
Change in FEV1 over time
Evidence that lung tissue has regenerated and is properly functioning
Trial Duration
3 Months for bronchodilators
6 Months for non-bronchodilators
6 Months 1 Year 3 Years Several Years
Comments
i.e. “Reduced Cough” must assess coughing subjectively or objectively
Seasonal Dependence makes trial duration extended
Cannot “parallel”disease progression after initial improvement
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Potential Catalysts for COPD Drug Discovery and Development
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Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE)
Sponsored by GSK, ECLIPSE planned to recruit 2,180 COPD subjects in Global Initiative for Chronic Obstructive Lung Disease categories II–IV and 343 smoking and 223 nonsmoking control subjects. Study procedures are to be performed at baseline, 3 months, 6 months and every 6 months thereafter for 3 years.
The study is expected to conclude 4Q09, however, GSK has started to publish early findings including preliminary studies of potential biomarkers for epithelial repair, COPD diagnosis and disease progression (CC-16), and exacerbation risk (SP-D).
Clearly, ECLIPSE has the potential to shed some light on current problems faced by clinicians and drug developers by providing better tools for disease classification, prognostication, treatment selection, and drug screening/testing. It may also help to generate new drug development hypotheses and therapeutic targets.
Eur Respir J. 2009 Jan 22. [Epub ahead of print] ; Thorax 2008;63;1058-1063; Eur Respir J 2008; 31: 869–873
ECLIPSE Study Procedures
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Network-Based Drug Discovery?
Nat Rev Drug Discov. 2009 Apr;8(4):286-95.
“The large-scale generation and integration of genomic, proteomic, signaling and metabolomic data are increasingly allowing the construction of complex networks that provide a new framework for understanding the molecular basis of physiological or pathophysiological states. Network-based drug discovery aims to harness this knowledge to investigate and understand the impact of interventions, such as candidate drugs, on the molecular networks that define these states,” Schadt, Friend, and Shaywitz(2009).
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Future Approaches To Therapy
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COPD & Asthma Development Pipeline
Asthma Both COPD
PC I II III Prereg Reg MarketCOPD Only 31 17 32 4 1 0 18Asthma Only 84 30 49 17 3 5 54Both 42 7 27 3 5 1 21
Adis R&D Insight 6/2009
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COPD Pipeline - Active Life-cycle Management
Adis R&D Insight 6/2009
Mechanism PC PI PII PIII Prereg Reg Launched I-IIILABA 2 0 8 0 1 1 9 8
LAMA 5 2 6 2 1 0 2 10
LABA/LAMA 2 1 4 0 0 0 0 5
ICS 1 0 0 0 0 0 6 0
LABA/ICS 0 0 2 1 0 0 3 3
LAMA/ICS 1 0 0 0 0 0 0 0
The development is focused on combinations of bronchodilators and corticosteroids, as well as ultra-long acting beta-agonists and anticholinergics.
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COPD Pipeline - Novel Anti-inflammatory Mechanisms
ADIS R&D Insight 6/2009
Mechanism PC I II III Prereg Reg Launched I-III
PDE4 inhibitors 10 0 5 0 1 0 0 5
Prostaglandin D2 receptor antagonists 1 2 2 0 0 0 1 4
Leukotriene antagonists 0 0 1 0 0 0 1 1
IL-13 receptor antagonists 0 0 1 0 0 0 0 1
Leukocyte elastase inhibitor 0 0 4 0 0 0 0 4
Adenosine receptor antagonists 4 1 0 0 0 0 0 1
p38 MAPK inhibitors 2 0 3 0 0 0 0 3
CCR/CXCR antagonists 1 0 0 0 0 0 0 0
TNF antagonists 1 0 0 0 0 0 0 0
5-lipoxygenase inhibitors 1 0 2 0 0 0 1 2
IL-8 (CXCR2) receptor antagonists 1 0 1 0 0 0 0 1
MMP inhibitors 2 0 1 0 0 0 0 1
Interferon stimulants 0 1 0 0 0 0 1 1
PI3K inhibitors 0 0 1 0 0 0 0 1
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Still Unproven Routes of Development
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PDE-4 Inhibitor Multiple Pathway Approach
Nature Reviews Drug Discovery, Oct 2004
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PDE-4 Inhibitors in DevelopmentRoflumilast (pre-registration EU, Phase III US Nycomed). ■ Balanced PDE-4 D & B inhibition. Good anti-inflammatory but weak
bronchodilating effects compared to theophylline■ Oral, QD dosing■ A study of 1440 moderate to severe COPD patients, demonstrated a
therapeutic effect on FEV1 (GOLD III& IV) and improvement in QoL and exacerbation frequency versus placebo (GOLD IV only)
■ Use maybe with LABA’s instead of ICS (that increase the risk of LRTI’s)
A number of other products in development■ Tetomilast (Phase II, Otsuka), Arofylline (Phase II, Almirall); GSK
256066 (Phase II, GSK – Inhaled); Oglemilast (Phase II, Glenmark); GPD-1116 (Phase I, Biotie)
Calverly PMA et al, Am J Respir Crit Care Med 2007, Adis R&D 6/2009
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TNF-α
TNF-α has a principal role in lung inflammation – maintains neutrophilic inflammation locally in airways and lung parenchyma and systemically by ‘inflammatory’ weight lossSignificantly higher levels of TNFα are found in people with COPD and weight loss compared to a matched population of healthy volunteersTNF levels inversely correlate to Pa02 and increased dyspnea severity
Nature Reviews Drug Discovery, June 2002
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TNFαEarly studies promoted by early preclinical data and empiric observation of improved outcome in rheumatoid arthritis patients with COPD treated by TNFα’s –halving of the hospitalization rate.
Two products trialed in respiratory disease – etanercept (Enbrel) and infliximab
Etanercept has been evaluated more in severe asthma and infliximab in various severities of COPD
In severe asthma etanercept or infliximab can improve respiratory symptoms and lung function, plus reduce exacerbations and airways inflammation on a short-term basis
Infliximab given long-term has been shown to improve outcomes such as exercise capacity in younger and more cachetic subjects with more advanced disease
TNFα safety concerns include serious infections – Tuberculosis
In the U.S. 144 TB cases in 100,000 patients (1998 – 2002) were reported. 72% occurring ≤ 90 days after therapy is a reason for caution in the COPD population
Suissa S. et al. Pulm Pharmacol Ther 2008, Wallis RS et al Clin Infect Dis 2004,
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© Defined Health, 2009Ligand Pharmaceutical 8k Report (02/2009)
IL8 - CXCR2 and CXCR1 AntagonistsWhile IL-8 has been the focus of many studies, other chemokine receptor ligands appear to be activated in COPD (CXCL1, CXCL5), and capable of modulating neutrophilic inflammation.
Redundant signaling modalities may explain the disappointing failure of Abgenix’s anti-IL8 monoclonal antibody therapy in psoriasis and COPD.
A few companies have now shifted there focus from ligand to the receptor. Schering-Plough has recently completed (4Q09) a phase II trial of its CXCR2 (SCH 527123), which represents the first true test of CXCR inhibition in COPD. The study results are highly anticipated.
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Old Drugs, New Strategies for COPD
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Antibiotics – Prophylactic Therapy for Prevention of Acute Exacerbations
http://www.clinicaltrials.gov; Am J Respir Crit Care Med. 2008 Dec 1;178(11):1098-9.
Bayer, Oral Moxifloxacin, Phase III
NHLBI, Oral Azithromycin
Mpex, Inhaled Levofloxacin, Phase II
The vicious-circle hypothesis contends that microbial colonization is significant to the development of COPD exacerbations and progression.
A recent study (109 pts) showed that daily intake of macrolide antibiotics (erythromycin) reduce exacerbation frequency by ~35% (moderate-to-severe COPD), suggesting that prophylactic antibiotic therapy may be used to disrupt the circle. Several larger studies are currently underway, with results expected later in 2009/2010.
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Theophylline – Stimulation of HDAC Activity for the Reversal ICS Resistance
Thorax. 2009 May;64(5):424-9. Epub 2009 Jan 21; Eur Respir J. 2009 May;33(5):1010-7. Epub 2009 Feb 5. Argetna Discovery Website
There is mounting evidence that theophylline may reverse corticosteroid resistance through its action of HDAC2 expression, which has implications for the treatment of resistant asthma and COPD. Recently, a study of smoking asthmatics showed that the theophylline/ICS combination improved symptoms and lung function to a greater extent than either single agent.
Argenta Discovery is hoping to harness this synergy and improve theophylline’s tolerability through the development of an inhaled theophylline/budesonide formulation (Phase I, EU).
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Statins - Pleiotropic Effects May Reduce COPD-Associated Morbidity and Mortality
Statins have consistently been associated with reduce morbidity and mortality, although the clinical evidence is largely derived from retrospective analyses.
They are believed to have antioxidant, anti-inflammatory, and immunomodulatory effects through the regulation of disease-associated cytokines, chemokines, and MMPs.
Chest 2007;131;1006-1012; Chest. 2009 Apr 17. [Epub ahead of print]
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Potential Ways Forward?
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Arachidonic Acid Metabolism
LTD4
LTE4
BLT1 BLT2
CysLT1
CysLT2
Focus of developmentactivity
Prostaglandins & other Lipid Mediators 2002
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5-Lipoxygenase: converts arachidonic acid into the unstable epoxide LTA4.
Ph II: Asthma, COPD
Phospholipase A2: liberates arachidonic acid from membrane phospholipids.
Ph II: Asthma
Ph II/III: Asthma, Atherosclerosis
Arachidonic Acid Metabolism - Drugs in Development
Leukotriene A4 Hydrolase: converts LTA4 into LTB4.
PC: Asthma, atopic dermatitis, IBD
Leukotriene C4 Synthase: converts LTA4 into LTC4.
Efficacy ?
Safety ?Adis R&D Insight
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PI3K Signaling in Steroid Resistance
Theophylline is an old drug that re-sensitizes COPD patients to corticosteroids, but is seldom used anymore due to adverse effects.Recently, it has been shown that
theophylline targets PI3Kδ, and that PI3K inhibitors can inhibit oxidative stress-induced reduction of HDAC2.Development of PI3Kδ-specific inhibitors, or inhibitors further downstream in the PI3K signaling pathway, could potentially yield a drug which has the efficacy of theophylline but not the side effects.
www.annualreviews.org • Role of HDAC2 in the Pathophysiology of COPD
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Conclusions
COPD is a growing problem with a high rate of morbidity and mortality.
Smoking cessation and Oxygen therapy are the only interventions with documented mortality benefit.
Immunological pathways and their inter-relationships not fully understood.
Novel approaches using these pathways not yet producing a major clinical benefit.
A 3 product approach (ICS/LABA/LAMA) using established products will bring greater symptomatic relief but not be disease modifying. A QD dosage regimen will greatly help patients obtain the maximum benefit and compliance with therapy.
A disease modifying agent is still the ‘holy grail’ everyone seeks