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.”