June 15, 2008 (Vol. 28, No. 12)

Sue Pearson Ph.D. Freelance Writer GEN

Delivery and Patient Compliance Are Central to Asthma, while New Therapies Are Key to COPD

Asthma and chronic obstructive pulmonary disease (COPD) are becoming more common throughout the world especially in countries such as India and China. So the potential for treating these diseases is enormous, said Peter Barnes, head of respiratory medicine, Imperial College, London (www3.imperial.ac.uk), at the recent SMI conference on “Asthma and COPD”.

“Both involve obstruction and inflammation of the airways but have different clinical presentations that require different treatments. Therefore, it is an enormous challenge to find new therapies, and I think it will be difficult to develop better asthma treatments in the next 20 years,” Professor Barnes continued.

Keith Allan, head of global advocacy at Novartis (www.novartis.com), concurred. “There haven’t been any novel asthma drugs in the past 20 years, and there are no prospects for any in the next 20 years for mild-to-moderate cases. The major challenge in this disease lies elsewhere, and that is in improving drug delivery and compliance.”

Size and Delivery Matter

Many of the technologies presented at the conference reflected this view and focused on methods of improving drug delivery and compliance to treat asthma. “Asthma is graded according to severity in five steps. In studies, the majority of patients are step 1 and 2 asthmatics, and over 55 percent of them have poorly controlled disease where they suffer attacks because they don’t take their medication properly,” reported Ewan Walters, medical director at Teva UK(www.tevauk.com). “In fact, only 20 percent of asthmatics take their steroids regularly because they feel well most of the time, and since the effect of taking steroids is cumulative and preventive, it is difficult for patients to see why they need to take them, so they don’t.”

Patient compliance was one of the two most pressing issues that emerged at the conference. The other was that not enough of the drug was actually getting into the lungs. Activaero (www.activaero.de) is addressing the delivery issue with its AKITA controlled breathing system.

“AKITA can be set for specific inspiratory flow rates and volumes to target therapeutic aerosols to different areas of the lungs,” explained Axel Fischer, managing director. “The AKITA is controlled by a smart card that determines the optimum breathing pattern for each patient and dosing requirements of a specific drug. Data about inhalation patterns and compliance can be recorded on the card and retrieved using a card reader and software.”

In a study using the AKITA with 72 cystic fibrosis patients over six weeks, the smart cards analyzed by Activaero showed 89% total dose compliance (patients achieving the correct number of inhalations), and 85% of patients inhaled regularly, thus also completing the daily schedule correctly. “AKITA can be used in early clinical trials because the device can help target the product more accurately to improve delivery. Additionally, improved transparency with patient compliance in a clinical trial provides for better understanding of the outcome,” Fisher concluded.

COPD—the Poor Relation?

Professor Barnes echoed the sentiments of many speakers at the conference by noting that since there are only poor treatments available for COPD and no effective anti-inflammatory drugs, it makes sense that this is where the most drug development should be targeted. COPD is generally treated with steroids, antibiotics, oxygen, and mucolytic (mucus thinning) therapies.

Topigen Pharmaceuticals (www.topigen.com) was one of the few companies presenting on drug development for asthma and COPD. The firm is developing a number of single-stranded oligonucleotides that inhibit validated mRNA targets in these diseases. “Oligonucleotides are a broad class of emerging therapeutics that include antisense, immunostimulatory oligos, decoys, and RNAi,” explained Mark Parry-Billings, Ph.D., chief development officer at Topigen.

“Since asthma and COPD are inflammatory diseases with multiple targets to attack it is difficult to find a magic bullet, which is why our inhalation candidates including TPI 1100 have two components. One is a single-strand 19 mer to target phosphodiesterase 4B and 4D mRNA, and the other is a 21 mer against phosphodiesterase 7A.”

According to Dr. Parry-Billings, in each oligonucleotide the ribose sugar is also replaced by a modified arabinose to give the molecule more potency and a longer duration of action. Based on positive preclinical findings, Topigen plans to work toward implementing Phase I studies with this molecule in the near future.

Again, based on a two oligonucleotide combination, Topigen is also developing TPI ASM8 for treating asthma. This drug candidate contains a 21 mer that targets mRNA for chemokine receptor 3 and another 19 mer that targets IL3, IL5, and GM-CSF mRNA. Dr. Parry-Billings presented results from a Phase II study in which 17 patients with asthma were given once-daily TPI ASM8 for four days.

TPI ASM8 was shown to reduce eosinophil influx into the lungs and also provide protection against both the early and late asthmatic responses in patients with mild-to-moderate asthma, Dr. Parry-Billings said. “There is a real need for effective, well-tolerated, more convenient alternatives for patients who are refractory to steroids. This study showed that TPI ASM8 would be a good second-line treatment in moderate and severe asthmatics who don’t respond to steroids and also a good alternative to monoclonals because it is convenient and inexpensive compared to this therapy class.”

Synairgen (www.synairgen.com) is using interferon beta (IFNb) as an antiinflammatory to treat asthma and COPD. According to Phillip Monk, Ph.D., head of development at Synairgen, the common cold virus (rhinovirus) triggers the worsening of asthma symptoms, with as many as eight out of 10 asthma-related emergency department visits being associated with these viral infections.

Additionally, up to 60% of all COPD exacerbations are preceded by the common cold. “Asthmatics are no more likely to get a cold than nonasthmatics but the difference is that both asthmatic and COPD subjects are more likely to develop lower respiratory tract infection and symptoms that drive exacerbations of respiratory disease,” Dr. Monk added.

Dr. Monk showed data from in vitro models in which researchers found that both asthmatic and COPD primary bronchial epithelial cells were more susceptible to infection with the rhinovirus than those from control subjects. Exogenous application of the antiviral cytokine IFNb normalized the response of asthmatic and COPD cultures preventing viral replication and cytopathic cell death.

“The increased susceptibility of asthmatic and COPD cells to viral infection offers an explanation for the increased likelihood of lower respiratory symptoms following a cold,” Dr. Monk said. “Synairgen is investigating the application of inhaled IFNb to reduce cold virus-induced exacerbations in both indications. We completed a Phase I trial in atopic non-asthmatic subjects and are preparing for a second multiple dose study in controlled asthmatic subjects that will begin later this year.”

The message from the “Asthma and COPD” conference was loud and clear: asthma medication, while not perfect, is adequate but requires better delivery and patient compliance to improve its efficacy. “Studies show 82 percent of patients who die from asthma have significant psychosocial behaviors such as poor compliance, denial, or depression; in other words if you continue smoking and taking medication incorrectly, you’re much more likely to die from asthma,” Dr. Walters concluded.

With COPD, on the other hand, drug development really needs to be stronger. “Of COPD patients who have had more than four exacerbations, 80 percent are dead within five years, so treatment options for these people are not working at all,” noted Steve Pascoe, Ph.D., global head, respiratory/dermatology profiling exploratory clinical development, Novartis. “I believe for small biotechs there is a real opportunity to develop effective anti-inflammatory drugs to treat COPD.”

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