**4. Conclusions**

448 Chronic Obstructive Pulmonary Disease – Current Concepts and Practice

comparisons between doses were not made, as it seemed that patients receiving the higher dose had better and earlier responses in most outcomes the daily dose of Daxas/Daliresp of 500 µg was then used in two subsequent identical trials (RATIO and OPUS). In these studies the patients had more severe COPD than in the RECORD study (postbronchodilator FEV1 of 50% or less, FEV1:FVC ratio of 0.7 or less, or FEV1 reversibility of 5% or less). Although completed, the results from the OPUS trial have not been published, however results from the RATIO study showed an improvement for the change from baseline for post bronchodilator FEV1, yet again no effect on the SGRQ (Calverley et al. 2007). A post-hoc analysis of a subgroup of patients with GOLD stage IV disease in the RECORD study showed a significant effect on reduction of exacerbation frequency (Calverley et al. 2007) which then led to the design of two identical studies AURA and HERMES where patients had a diagnosis of clinical COPD (confirmed by postbronchodilator FEV1/FVC of at least 70%, and a FEV1 at least 50% of predicted), had symptoms of chronic bronchitis and a history of exacerbations. Patients experienced an improvement in pre- and postbronchodilator FEV1 and a reduction in exacerbation rate (Calverley et al. 2009) which were independent of LABA

Taken together, the Daxas/Daliresp studies clearly show effects in patients with GOLD stage IV disease, with focus on measuring flow rates and exacerbation reduction as parameter outcomes. The clinical program for PXS TPI1100 can use this information in designing studies so as to sharply define the patient population at the onset and include the

As ICS and LABA have been shown to be more effective at improving lung function, health status and reducing COPD exacerbations when combined than when used individually (Calverley et al. 2007) the effect of combining Daxas/Daliresp with either the long-acting β2 agonist salmeterol (EOS study) or the long-acting inhaled antimuscarinic tiotroprium (HELIOS study) was studied in patients with less severely reduced lung function as compared to the previous studies. Results showed that the pre- and postbronchodilator FEV1 improved in patients treated with Daxas/Daliresp versus placebo when combined with either LABA or LAMA (Fabbri et al. 2009). PXS TPI1100 can be expected to also function in combination with LABA, similar to that demonstrated by Daxas/Daliresp and

As with any drug, adverse events to Daxas/Daliresp were reported which included weight loss, diarrhea, nausea, headache, influenza and nasopharyngitis as well as certain cancers such as lung and prostate (Giembycz &Field 2010). There was a greater risk of discontinuation of therapy within the first 12 weeks of treatment for those patients taking Daxas/Daliresp than placebo although by the end of the studies, similar numbers of patients withdrew in both groups. In the Daxas/Daliresp treated groups, the most common reason for withdrawal were

There are aspects of PXS TPI1100 which may lend itself advantages over Daxas/Daliresp. Firstly, as PXS TPI1100 is administered via inhalation, it is delivered directly to the intended site of action of the lung (Ali et al. 2001; Duan et al. 2005; Gauvreau et al. 2008; Guimond et al. 2008) where the drug can enter target cells directly (Zhang et al. 2004; Griesenbach et al. 2006) thus potentially reducing total dose as compared to orally-available treatments. A further advantage of pulmonary administration of AON is that they are principally

the gastrointestinal adverse events or headache (Giembycz &Field 2010).

use, but no differences in mortality or C-reactive protein levels.

key primary outcomes as success measures.

could potentially replace ICS.

PXS TPI1100 faces challenges, in part of being the first respirable antisense drug product in COPD. As COPD is a chronic disease, it can be expected that patients will be dosed for years. The long-term effects of this drug class have never before been studied. In addition, in pulmonary/respiratory diseases, there is a risk that administration of therapeutic nucleic acids may lead to immune stimulation, inflammation and possibly hypersensitivity and bronchoconstriction of the airways. Except for the latter, these risks are not specific to the lung as they have been observed with other routes of administration. As with any novel inhaled medication, local tolerability and the absence of long-term effects following chronic dosing will require careful evaluation as drug candidate progresses through the later stages of development. The publicly available toxicological data on inhaled AON are not extensive (Guimond et al. 2008), and therefore deriving definitive conclusions on toxicology at this time is not possible. The phase 2a studies that have been performed until now have not shown any of this potential toxicity but longer term studies are needed to confirm these results. Furthermore, to date AON have been delivered via inhalation of a nebulisate to asthma patients (Gauvreau et al. 2008; Gauvreau 2010), but not to COPD patients who have severely decreased FEV1. How well this patient cohort inhales the nebulisate would need to be determined. The range of delivery devices (including newer portable soft-mist inhalers) have increased and permit liquid aerosols to be targeted more effectively to the specific airways of interest (upper or lower airways), improve ease of use by patients and would be expected to improve compliance to therapy. In contrast, the particle processing and formulation of AON for delivery in dry powder inhalers or pressurized metered dose inhalers, which are most commonly used by COPD patients has, however, proven to be significantly more challenging than that of liquid aerosols.

Another challenge facing PXS TPI1100 is the selection of its targets PDE4B/D and PDE7A. While the success of Daxas/Daliresp demonstrates the effectiveness of targeting PDE4 in COPD, to date there is less corrobative clinical evidence for the efficacy of targeting PDE7A isoform. The success or failure of a specific drug development program is determined by a range of different factors, which includes the clinical relevance of the selected drug target.

A Multi-Targeted Antisense Oligonucleoitde-Based

pp.14188-14192

201563OC

3692 (Print)

CRC Press, Boca Raton FL

578 1073-449X (Print)

*Br J Pharmacol* Vol.148 No.(3): pp.245-254

*Pharmacol* Vol.153 Suppl 1 S446-456

Therapy Directed at Phosphodiesterases 4 and 7 for COPD 451

Barnes, P. J. (2006). How corticosteroids control inflammation: Quintiles Prize Lecture 2005

Bateman, E. D., Hurd, S. S., Barnes, P. J., Bousquet, J., Drazen, J. M., FitzGerald, M., Gibson,

Bender, A. T. and Beavo, J. A. (2006). Cyclic nucleotide phosphodiesterases: molecular

Bloom, T. J. and Beavo, J. A. (1996). Identification and tissue-specific expression of PDE7

Brown, R. A., Spina, D. and Page, C. P. (2008). Adenosine receptors and asthma *Br J* 

Calverley, P. M., Anderson, J. A., Celli, B., Ferguson, G. T., Jenkins, C., Jones, P. W., Yates, J.

Calverley, P. M. A., Sanchez-Toril, F., McIvor, A., Teichmann, P., Bredenbroeker, D. and

Caramori, G., Romagnoli, M., Casolari, P., Bellettato, C., Casoni, G., Boschetto, P., Chung, K.

Cazzola, M., MacNee, W., Martinez, F. J., Rabe, K. F., Franciosi, L. G., Barnes, P. J., Brusasco,

from lung function to biomarkers *Eur Respir J* Vol.31 No.(2): pp.416-469 Cowburn, A. S., Condliffe, A. M., Farahi, N., Summers, C. and Chilvers, E. R. (2008).

Crooke, S. T., Ed. (2008). *Antisense Drug Technology: Principles, Strategies and Applications*,

David, M., Zech. K., Seiberling, M., Weimar, C. and Bethke, TD. (2004). Roflumilast, a novel,

Down, G., Siederer, S., Lim, S. and Daley-Yates, P. (2006). Clinical pharmacology of

Duan, W., Chan, J. H., McKay, K., Crosby, J. R., Choo, H. H., Leung, B. P., Karras, J. G. and

*and Clinical Immunology* Vol.113 No.(suppl 2): pp.S220-221

Cilomilast *Clin Pharmacokinet* Vol.45 No.(3): pp.217-233

GINA executive summary *Eur. Respir. J.* Vol.31 No.(1): pp.143-178

regulation to clinical use *Pharmacol Rev* Vol.58 No.(3): pp.488-520

randomised clinical trials *Lancet* Vol.374 No.(9691): pp.685-694

COPD exacerbations *Thorax* Vol.58 No.(4): pp.348-351

P., Ohta, K., O'Byrne, P., Pedersen, S. E., Pizzichini, E., Sullivan, S. D., Wenzel, S. E. and Zar, H. J. (2008). Global strategy for asthma management and prevention:

phosphodiesterase splice variants *Proc Natl Acad Sci U S A* Vol.93 No.(24):

C. and Vestbo, J. (2007). Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease *N Engl J Med* Vol.356 No.(8): pp.775-789 Calverley, P. M., Rabe, K. F., Goehring, U. M., Kristiansen, S., Fabbri, L. M. and Martinez, F.

J. (2009). Roflumilast in symptomatic chronic obstructive pulmonary disease: two

Fabbri, L. M. (2007). Effect of One Year Treatment with Roflumilast in Severe Chronic Obstructive Pulmonary Disease *Am. J. Respir. Crit. Care Med.* Vol.200610-

F., Barnes, P. J., Adcock, I. M., Ciaccia, A., Fabbri, L. M. and Papi, A. (2003). Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during

V., Burge, P. S., Calverley, P. M. A., Celli, B. R., Jones, P. W., Mahler, D. A., Make, B., Miravitlles, M., Page, C. P., Palange, P., Parr, D., Pistolesi, M., Rennard, S. I., Rutten-van Molken, M. P., Stockley, R., Sullivan, S. D., Wedzicha, J. A., Wouters, E. F. and on behalf of the American Thoracic Society/European Respiratory Society Task Force on outcomes of, C. (2008). Outcomes for COPD pharmacological trials:

Advances in neutrophil biology: clinical implications *Chest* Vol.134 606-612 0012-

oral, selective PDE4 inhibitor, shows high absolute bioavailabilty. *Journal of Allergy* 

Wong, W. S. (2005). Inhaled p38alpha mitogen-activated protein kinase antisense oligonucleotide attenuates asthma in mice *Am. J. Respir. Crit. Care Med.* Vol.171 571-

One early pioneer in the respiratory field was the AON drug EPI 2010 (Epigenesis) targeting the promoter region of the adenosine A1 receptor. Although demonstrating efficacy *in vitro* and in animal models (Ball et al. 2004), EPI 2010 failed in later clinical studies to demonstrate efficacy to improve lung function in asthmatics. With the more recent understanding of the role the different adenosine receptors have in asthma (Brown et al. 2008), it could be argued that the absence of clinical efficacy for EPI 2010 could either be a result of targeting the wrong adenosine receptor or perhaps the need to combine it with other adenosine receptor inhibitors. Similarly, early preclinical efficacy and effect on biomarkers in a phase 1 study with AIR-645 (AON targeting IL-4/IL-13Rα Altair/Isis) met with apparent insufficient efficacy on lung function in phase 2 study (personal communication). This may perhaps be attributed to the target selection as other non-ODN drugs targeting these receptors have also had limited success in clinical trials. As mentioned, although few PDE7 inhibitors have been tested in clinical studies, our preclinical pharmacology results indicate a clear benefit in targeting this PDE isoform along with the PDE4. There is growing acceptance that multitargeted approaches may provide significant therapeutic advantages, as demonstrated by the issuance of new guidance on drug combinations by the Food and Drug Administration.

There is a clear need for innovative products with novel mechanisms of action to complement today's inhaled products particularly for severe patients who seem resistant to current therapeutic interventions. In spite of many attempts, success in these respiratory indications has been modest, at most. This may reflect the challenge of delivering the therapies to the site of action (lung) or more importantly the complexity of these diseases. PXS TPI1100 belongs to a new class of therapeutics that is poised to expand in the upcoming decades because of its advantages, especially with lung administration. Outstanding challenges for PXS TPI1100 remain the need to establish long term safety and tolerability data as well as commence clinical efficacy. The future remains very promising for this novel drug.

#### **5. Acknowledgements**

The authors wish to thank Drs. Ian McDonald, Wolfgang Jarolimek and Gary Phillips for critical review of the manuscript.
