**3. Conclusions**

*S. pneumoniae* remains a major cause of morbidity and mortality worldwide. There are different preventive options but, at the moment, none is optimal. Among patients with chronic respiratory diseases, pending other more effective antipneumococcal vaccines, the PPV-23 (together with influenza vaccine) is currently the only preventive approach that has demonstrated an effect, even if it does not match up to expectations (Gaillat 2009).

COPD patients are commonly described as an at-risk population for pneumococcal infections, but RCTs on PPV efficacy in such patients are very limited and largely underpowered to obtain a reliable conclusion about the efficacy of the vaccine. Among the general population, most meta-analyses have concluded that the PPV is effective against IPD among immunocompetent persons. Recommendations for vaccinating COPD patients are based on this data, although the evidence for vaccine efficacy is less clear among persons with comorbidities.

Among COPD patients, the effectivenes of vaccination in preventing pneumonia and/or acute infective exacerbations is unclear. Two meta-analyses focused on COPD patients concluded that, although it is possible that PPV may provide some protection in persons with COPD, no significant protective effects were demonstrated in the meta-analysis. Considering nonRCTs, the clinical effectivenes of vaccination is also uncertain, but several studies have reported distinct benefits from pneumococcal vaccination in preventing distinct respiratory infections (using the PPV-23 alone and/or together with influenza vaccine).

Several studies have shown that the PPV-23 is cost-effective for preventing IPD among the general population over 65 years in developed counttries, but there is no data about costeffectiveness of vaccination among COPD patients given the lack of efficacy data in these persons. Current CDC's recommendations for using PPV-23, besides COPD, include smoking and asthma. Revaccination (5-10 years after prime dose) is recommended for those persons who received PPV-23 before 65 years of age. It must not be forgoten, however, that the PPV-23 provides incomplete protection, it does not elicit long-lasting immunity, and no anamnestic effect occurs at revaccination. So, more effective vaccination strategies are needed.

In the next few years, the results of ongoing trials evaluating the efficacy of the PCVs in adults will be critical in determining the position of the conjugate vaccine in the prevention of pneumococcal diseases in patients with chronic respiratory diseases. In coming years, new PCVs including progressively more serotypes (most likely emerging types due to epidemiological changes) will probably be needed. However, the serotype replacement phenomenon can not be fully overcome by increasing the number of serotypes, so new technologies, such as protein-based or genomic vaccines, will be greatly needed. Experimental protein-based pneumococcal vaccine candidates offer the potential advantage of serotypeindependent protection and several are in various stages of development in animal models, but none can be expected to be available in clinical practice for several years at least.

Until better options are available, the PPV-23 should continue to be used in high-risk individuals, including younger and older adults with COPD. Although only moderately effective, the burden of pneumococcal disease is greatest in these persons and they can obtain benefit from vaccination.

#### **4. References**

430 Chronic Obstructive Pulmonary Disease – Current Concepts and Practice

Theoretical major advantages for a future PbPV could be the serotype-independent protection, the possibility of oral or intranasal administration, and probably a less complex production process and a lower cost than conjugate vaccines. However, at the moment, information on humans is scarce, and many studies and several years will be needed to elucidate the true potential of PbPV in human prevention. If finally these proteins can not provide sufficient protection as a sole component of the vaccine, it is posssible that they could be used either as a carrier protein for a conjugate vaccine or as a supplement component for the current vaccines to provide additional protection against pneumococcal

*S. pneumoniae* remains a major cause of morbidity and mortality worldwide. There are different preventive options but, at the moment, none is optimal. Among patients with chronic respiratory diseases, pending other more effective antipneumococcal vaccines, the PPV-23 (together with influenza vaccine) is currently the only preventive approach that has

COPD patients are commonly described as an at-risk population for pneumococcal infections, but RCTs on PPV efficacy in such patients are very limited and largely underpowered to obtain a reliable conclusion about the efficacy of the vaccine. Among the general population, most meta-analyses have concluded that the PPV is effective against IPD among immunocompetent persons. Recommendations for vaccinating COPD patients are based on this data, although the evidence for vaccine efficacy is less clear among persons

Among COPD patients, the effectivenes of vaccination in preventing pneumonia and/or acute infective exacerbations is unclear. Two meta-analyses focused on COPD patients concluded that, although it is possible that PPV may provide some protection in persons with COPD, no significant protective effects were demonstrated in the meta-analysis. Considering nonRCTs, the clinical effectivenes of vaccination is also uncertain, but several studies have reported distinct benefits from pneumococcal vaccination in preventing distinct respiratory infections

Several studies have shown that the PPV-23 is cost-effective for preventing IPD among the general population over 65 years in developed counttries, but there is no data about costeffectiveness of vaccination among COPD patients given the lack of efficacy data in these persons. Current CDC's recommendations for using PPV-23, besides COPD, include smoking and asthma. Revaccination (5-10 years after prime dose) is recommended for those persons who received PPV-23 before 65 years of age. It must not be forgoten, however, that the PPV-23 provides incomplete protection, it does not elicit long-lasting immunity, and no anamnestic

In the next few years, the results of ongoing trials evaluating the efficacy of the PCVs in adults will be critical in determining the position of the conjugate vaccine in the prevention of pneumococcal diseases in patients with chronic respiratory diseases. In coming years, new PCVs including progressively more serotypes (most likely emerging types due to epidemiological changes) will probably be needed. However, the serotype replacement phenomenon can not be fully overcome by increasing the number of serotypes, so new

effect occurs at revaccination. So, more effective vaccination strategies are needed.

demonstrated an effect, even if it does not match up to expectations (Gaillat 2009).

(using the PPV-23 alone and/or together with influenza vaccine).

infections (Wright 2008).

**3. Conclusions** 

with comorbidities.


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**22** 

*Canada* 

**A Multi-Targeted Antisense** 

Rosanne Seguin and Nicolay Ferrari

*Part of the Pharmaxis Ltd. Group, Montréal, QC* 

*Topigen Pharmaceuticals Inc.,* 

**Oligonucleotide-Based Therapy Directed at Phosphodiesterases 4 and 7 for COPD** 

Recent drug development for chronic obstructive pulmonary disease (COPD) has focused on strategies aimed at reducing the underlying inflammation by selective inhibition of phosphodiesterases (PDE), specifically the PDE4 isoforms. The anti-inflammatory and bronchodilator activities of PDE4 inhibitors have been well documented (Giembycz &Field 2010), however their clinical development has been hampered by their low therapeutic ratio and dose-dependent systemic side effects. PXS TPI1100 is an inhaled drug candidate consisting of two modified antisense oligonucleotides (AON) directed at PDE isoforms 4B, 4D and 7A. PXS TPI1100 has been designed to reduce the recruitment and persistence of inflammatory cells in COPD through an unique mechanism of action and has the potential

In this chapter, we will present the rationale for the design of PXS TPI1100 including a summary of the PDE families and the proposed role they play in regulating inflammation in the lung. Next we will present an overview of the discovery and selection process for the drug candidate, including a summary of the key results from pre-clinical pharmacology, both *in vitro* models as well as two *in vivo* models of neutrophilic inflammation: cigarette smoke mouse model and LPS challenge model. These results will be compared to the first-in-class PDE4 inhibitor, roflumilast (Daxas/Daliresp). We shall conclude with the expected development plan for PXS TPI1100 including the design of

COPD is a respiratory disease of airway obstruction and lung damage and is sometimes called chronic bronchitis and/or emphysema. COPD kills millions of people each year and it is currently the fourth leading cause of death worldwide, with forecasts to be the third leading cause by 2020 (ref www.goldcopd.com). COPD, as defined by the Global Initiative for Chronic Lung Disease (GOLD) is *"a preventable and treatable disease with some extrapulmonary 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* 

to be a novel, highly effective approach for this respiratory disease.

**1. Introduction** 

upcoming clinical study trials.

**2. Chronic obstructive pulmonary disease** 

