getting beyond prevention inventive strategies for...

Getting Beyond Prevention

Inventive Strategies for COPDTim Joslin

Managing Director, Europe

Defined HealthWebinar 17th June, 2009

[email protected]

COPD Insight Briefing – June 2009Defined Health - Pg. 2

© Defined Health, 2009

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.




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:



Defined Health Areas of Experience and Expertise



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



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



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



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.



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



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?



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



Even with Explosive Epidemiology, Diabetes Represents < 15 Million ‘Diagnosed’ Cases in 2005

US Dept HHS



High but Variable COPD Mortality by Country

A ‘typically’ British

Disease?



Current Management



Management Algorithm for Mild COPD

International Journal of COPD 2008:3(4) 563–573



COPD Market Value – Major ClassesDriven by SpirivaChange to ICS/LABA

Combination Therapy



Current Management - Devices

COPD is a multi-billion dollar market defined by pulmonary inhalation devices delivering agents that provide only symptomatic relief.

http://images.google.com/imgres?imgurl=http://www.drugs.com/pro/images/688da899-590a-491c-909c-d140db07d849/serevent-diskus-pil-parts.jpg&imgrefurl=http://www.drugs.com/pro/serevent-diskus.html&usg=__wJ9NQnjT_5SNaGRbb4KGktnPT38=&h=288&w=432&sz=16&hl=en&start=1&um=1&tbnid=OdNhyUIBNjgtIM:&tbnh=84&tbnw=126&prev=/images%3Fq%3Dserevent%2Bdiskus%26um%3D1%26hl%3Den%26safe%3Doff%26rls%3DDAUS,DAUS:2006-08,DAUS:en

http://www.advair.com/index.html

http://images.google.com/imgres?imgurl=http://www.sk.lung.ca/drugs/images/respiratory/img000082b.jpg&imgrefurl=http://www.sk.lung.ca/drugs/pages/82.html&usg=__iEmC0aO0rwS_2EyJV5YXSU6tDCY=&h=291&w=215&sz=10&hl=en&start=4&um=1&tbnid=hOfdmjNFVwU8PM:&tbnh=115&tbnw=85&prev=/images%3Fq%3Dcombivent%26um%3D1%26hl%3Den%26safe%3Doff%26rls%3DDAUS,DAUS:2006-08,DAUS:en%26sa%3DN

http://images.google.com/imgres?imgurl=http://www.modernmedicine.com/modernmedicine/data/articlestandard/drugtopics/182008/514079/advair.jpg&imgrefurl=http://www.modernmedicine.com/modernmedicine/Community%2BPharmacy/GlaxoSmithKline-receives-approval-for-Advair-Disku/ArticleStandard/Article/detail/514079&usg=__X5s9agxHu34Ut8tmvpQzs3i0rI4=&h=293&w=300&sz=28&hl=en&start=1&um=1&tbnid=2nabxr2iW5WmhM:&tbnh=113&tbnw=116&prev=/images%3Fq%3Dadvair%26um%3D1%26hl%3Den%26safe%3Doff%26rls%3DDAUS,DAUS:2006-08,DAUS:en%26sa%3DN

http://images.google.com/imgres?imgurl=http://allergy.peds.arizona.edu/southwest/devices/inhalers-asthma/steroi6.jpg&imgrefurl=http://allergy.peds.arizona.edu/southwest/devices/inhalers-asthma/steroids_oral.htm&usg=__Il1rwW0a34vWBwUOxYiuSgqmgkU=&h=132&w=104&sz=3&hl=en&start=107&um=1&tbnid=45hO0kbD98IdSM:&tbnh=92&tbnw=72&prev=/images%3Fq%3Dsymbicort%26start%3D90%26ndsp%3D18%26um%3D1%26hl%3Den%26safe%3Doff%26rls%3DDAUS,DAUS:2006-08,DAUS:en%26sa%3DN



Treatment Effects



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.



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.



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



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.



Benefits of Smoking Cessation



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.



Underlying Immunological Mechanisms



Asthma COPD

Barnes PJ, Nature Reviews immunology vol 8, March 2008



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



Current and Future Medical Needs



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



Regulatory & Trial Issues



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



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




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




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




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



Potential Catalysts for COPD Drug Discovery and Development



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



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).



Future Approaches To Therapy



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



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.



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



Still Unproven Routes of Development



PDE-4 Inhibitor Multiple Pathway Approach

Nature Reviews Drug Discovery, Oct 2004



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



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



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,


© 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.



Old Drugs, New Strategies for COPD



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.



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).



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]



Potential Ways Forward?



Arachidonic Acid Metabolism

LTD4

LTE4

BLT1 BLT2

CysLT1

CysLT2

Focus of developmentactivity

Prostaglandins & other Lipid Mediators 2002



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



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



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

getting beyond prevention inventive strategies for...

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