The COPD Pipeline

Smoking Cessation. Nabi Biopharmaceuticals has received a NIDA grant of $4+ million in partial support of the next and, one hopes, final phases of a possible nicotine conjugate vaccine. The agent, to be known as NicVax, stimulates the production of antibodies that bind nicotine and prevent it from entering the brain. A widely reported Phase II clinical trial provided proof-of-concept. The FDA has given the agent ‘fast track’ designation and a Phase III trial will be underway shortly.

Acute Exacerbations of COPD. I will report on recent developments in two aspects of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in this column, namely maintenance treatments for prophylaxis against AECOPDs and short-term treatments for AECOPD events.

Concerning the first, a reduction in the frequency and severity of AECOPDs is a major goal of research in COPD of-course. We already know that significant reductions in the frequency of AECOPD are obtained with maintenance use of long-acting inhaled bronchodilators, corticosteroids, flu vaccination, and possibly pulmonary rehab and theophylline. But are there beneficial modalities other than those? I found 5 “pipeline” items that seem worthy of mention.

1. Maintenance prophylaxis with oral antibiotics has not been found to reduce the frequency of AECOPDs despite many attempts since the beginning of the antibiotic era. But perhaps inhaled antibiotics would be effective; a Phase II trial of inhaled levofloxacin given on a recurring basis for 5 days every month was due to conclude in November 2009 (NCT00739648). Note: (NCT00XXXXX) = clinicaltrials.gov identifying number. Similarly, an inhaled formulation of aztreonam is being developed for CF. If successful, one supposes a COPD indication will follow.

2. Advances in pneumococcal vaccines are always being sought and there has been uncertainty about the efficacy of the conventional 23-valent vaccine (PPSV23) in immunocompromised subjects such as COPD patients. A more antigenic protein conjugate vaccine, PCV7, is being compared to the conventional vaccine in a Phase III trial aimed specifically at COPD patients (NCT00457977). The active phase of the trial, which is sponsored by NIH, is due to complete in May 2010.

3. Much earlier in development is a combination vaccine against non-typeable H. influenza and S. pneumoniae also targeted specifically for COPD patients (NCT00849069).

4. Previous attempts to reduce the frequency of AECOPD by promoting mucociliary clearance and airway hygiene with “mucolytic therapy” have not been impressive. For agents such as iodinated glycerol, streptokinase, urokinase, rhDNAse, dornase alpha (Pulmozyme), ambroxol, and N-acetyl cysteine, “the overall benefits seem to be very small” in the words of the GOLD report. Nevertheless, the search terms “mucolytic” and “expectorant” elicit 123 entries on the clinicaltrials.gov website. A potential agent that was not found on the website is carbocisteine. Carbocisteine has been previously reported to limit mucin production, scavenge oxygen radicals, and reduce the frequency of AECOPD. In fact it received a gentle nod from the 2008 version of the GOLD report. A randomized controlled trial from China (Lancet 2008; 371:2013–18) found that this agent significantly reduced the frequency of AECOPDs in patients with GOLD stage II-III COPD. In view of the unmet need for an oral mucolytic agent that works well it seems likely that carbocisteine could become a candidate for development for the indication of AECOPD prophylaxis.

5. Now that noninvasive ventilation (NIV) has been widely studied and is being widely used to both clinical and financial benefit, it is not unexpected that its potential for chronic outpatient use in advanced stages of COPD is being explored. NCT00429156 is a Phase III RCT of non-invasive ventilation at home following AECOPD to determine if it will “reduce the likelihood of death and recurrent respiratory failure requiring NIV or intubation.” In fact, there are at least 6 very similar studies on the clinicaltrials.gov site, which will measure a similar outcome. I cite this one only because it first appeared in October 2009, the time when this column is being written.

For the management of the AECOPD event itself, I found four items of interest:

1. During the acute phase of an exacerbation, retention of airway secretions and mucus is seen as a problem. As in stable COPD, previous attempts to address this concern have met with little success. However, the rationale that increasing the mobility and clearance of mucoid airway secretions by inhalation of an osmotic agent is being tested again. A dry powder formulation of mannitol, Bronchitol (Pharmaxis), which has been shown to reduce the frequency of acute exacerbations of cystic fibrosis and bronchiectasis, has completed an open-label phase I-II trial in AECOPD (NCT00446667). No results have been published at the time of writing.

2. Etanercept, the TNF-alpha receptor blocker is receiving a Phase II-III double-blind, double-dummy RCT in AECOPD (NCT00789997). Although a different anti-TNF-alpha agent, infliximab, was ineffective and even problematic in trials for stable COPD and severe asthma, the concept of short-term use of a TNF-alpha blocker in AECOPD seems worthy of exploration. One applauds the trial sponsors, Ottawa Hospital Research Institute, for having the courage to use a proven, active control, prednisone 40 mg q.d., rather than placebo. The study is due to complete in September 2010.

3. Further upstream, one's interest is aroused by two oral DP2 receptor antagonists from Amira, AM211 and AM461, that successfully completed Phase I trials last year. Their action, which is to inhibit eosinophil chemotaxis in the airways, may be most relevant to the treatment of acute asthma. However, this action may also be appropriate for AECOPD, which is also stated as a target indication.

4. Not strictly a drug, but a treatment for AECOPD, NIV is widely used for AECOPD in hospitalized patients. But can its early, ‘pre-hospital’ use reduce the need for hospitalization? A randomized open-label study from Belgium will examine its use in “Out-of-Hospital patients” to determine whether NIV with standard therapy results in a lower failure rate than standard therapy alone (NCT00375154). The logistics of obtaining informed consent and baseline data and then administering NIV to out-of-hospital patients with AECOPD and acute respiratory failure seem daunting. The study was initiated in 2006 and no data are yet available (Information kindly provided by Prof Frederic Thys, Louvain).

Devices for COPD

1. Endobronchial valves (Thanks to Dr. Charlie Strange for helpful information and advice for the sections on valves and hydrogel). At least 3 types of one-way endobronchial valves have been in trials for COPD for some years. Spiration has the IBV valve system, and Pulmonx has the EBV system (due to their takeover of Emphasys, and known as Zephyr. An earlier Emphasys valve known as Transcopic was discontinued). Designed to provide a less invasive alternative for lung volume reduction than surgery, both valves, up to 4 on each side, are bronchoscopically placed in airways that serve lung regions that are emphysematous. Both have recently completed Phase III trials, (NCT00475007, 00995852, 00880724, NCT00129584). Results are awaited. The Zephyr valve is approved and available in some countries in Europe. The treatment experience has been heterogeneous, partly due to issues with collateral ventilation across lobar fissures. The safety data reported to date show a low incidence of valve dislodgement and post-obstructive pneumonia.

   A similar but different approach is the Broncus Exhale Airway Stent. This is a drug-eluting stent, up to 3 of which may be placed in each lung. Each stent is positioned bronchoscopically in a fenestration that is created between an airway and an adjacent hyperinflated region of lung parenchyma, allowing trapped gas to leave those regions. A 1-year, Phase III, double-blind, randomized, sham-controlled trial, called “EASE,” is underway (NCT00391612).

2. Hydrogel or AeriSeal is an agent being studied for “biologic lung volume reduction,” again, as a less invasive alternative to surgery. Under general anesthesia, separate dual-lumen catheter instillations of a suspension of fibrinogen and a solution of thrombin are endobronchially placed in target airways, those that lead to hyperinflated lung regions. The instillations are followed by a volume of air to force the mixture peripherally. The two agents react forming a fibrin clot that causes the hyperinflated region to collapse and eventually organize. Up to 4 regions in each lung are targeted. Some technical issues still need to be settled. An open-label Phase II study (Criner GR et al AJRCCM 2009; 179:791–8) found that, besides the expected lung volume changes, meaningful improvements in quality of life and 6-minute walk were obtained and maintained for 6 months. A “second generation” of the system is undergoing further study in Israel and several European countries. The system was recently given “fast track” status by the FDA and the company, Aeris, states that U.S. studies may begin the end of 2010.

3. Nebulizers for the delivery of aerosols to the lower respiratory tract are becoming smaller, quieter, able to deliver very small volumes very quickly and with minimal wastage in the nebulizer cup and tubing. Perhaps most important, they seem to be more efficient, delivering a high proportion of the medication in highly respirable droplets. Mostly this seems to be due to an advance in the technology from the familiar “jet” system to a vibrating mesh. Several companies make products using the latter technology, Aerogen, MicroAir and Omron are some. Not yet approved is Pari's eflow, which uses similar technology. One notes that many nebulizer products in development are being developed for use in conjunction with Pari's eflow, namely Kamada's new alpha-1agent, Mpex's Aeroquin, Gilead's aztreonam, as well as Pari's own tobramycin, cyclosporine and disodium cromoglycate. Drawbacks of the vibrating mesh nebulizers are their need for frequent scrupulous cleaning and, inevitably, at $200–300 each, greater expense.

Dual-Action Bronchodilators, MABAs (muscarinic antagonist beta agonist). In treating most chronic diseases including COPD, combinations of two therapies with different but complementary actions typically have advantages over monotherapies, a fact that we take advantage of in the clinic every day. (Indeed, triple combinations are already in clinical studies for COPD). In a further development, rather than combining two agents into a single inhaler, pharmaceutical chemists have been working to combine the actions of two different classes of agent into a single molecule. For a dual-action bronchodilator, the synthesis involves covalently linking a beta-2 agonist pharmacophore to an M3 muscarinic receptor antagonist pharmacophore. The clinical rationale is that convenience and thus compliance would probably be improved, and that patients cannot take one agent without taking the other. Additionally, issues such as the formulation, delivery, dose-response, and stability may be simplified for a single agent. Furthermore, regulatory approval for a combination of two new chemical entities is complicated, involving approval of each component separately as well as in combination, plus the Food and Drug Administration's combination rule.’ A single molecule that conferred both therapeutic effects might avoid some of those problems and may be a faster and less expensive route to regulatory approval. Most of the dual-action agents known to be in development combine two long-acting moieties, long-acting beta-2 agonist (LABA) and long-acting muscarinic antagonist (LAMA), into a muscarinic antagonist beta agonist (MABA), but there are some in which one of the components has some anti-inflammatory properties, either PDE4i-like or corticosteroid-like. I do not deal with those here.

Where are we with MABAs? The first patent applications were made by Theravance in 2004. Since then at least 11 more patents have been issued to several of the major players in the COPD field, AstraZeneca, Boehringer-Ingelheim, Pfizer, Novartis, and GlaxoSmithKline among them. At the time of writing, there appear to be 2 MABAs in human studies, the front-runner is GSK's GSK961081 which was licensed from Theravance, which completed a Phase I trial (NCT00674817) and is now in Phase II. AstraZeneca, in partnership with Argenta, also has a MABA that was due to enter Phase II late in 2009. Although there are meeting abstracts that detail their actions in cells and receptors in vitro, there is no clinical information in the public domain about either agent in humans at this time, or whether they will be once- or twice-daily drugs. One assumes the former.

I mentioned a few possible advantages of a MABA. What are the potential problems? The molecules will necessarily be relatively large and may present problems with handling and delivery. Bioavailability may be poor. One might also anticipate that some of the current safety concerns associated with current mono-component drugs of each class, box warnings, etc., may well be bestowed on the new dual action agents by regulatory agencies. If this were the case, it could wipe out much of the expected advantages of MABAs.

Declaration of interest

The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.