Smoking Cessation Drugs
We are all too aware of the problems associated with smoking and the difficulty of getting smokers to quit. We currently have 3 classes of drugs that address nicotine addiction, including nicotine replacement therapies, sustained-release bupropion, and varenicline, and some second-line treatments, including clonidine and nortriptyline. Although each is effective, the quit rates with each need to be higher and relapse rates are commonly in the 90% range. At the same time cigarette smoking is increasing, particularly in developing nations. The market for smoking cessation therapies is predicted to double by 2016 and there are no fewer than 15 drugs in Phase II or III development. They include candidates that target nAcetylcholine receptors, the dopamine D3 receptor, the cannabinoid 1 receptor, the MAO receptor, and 3 vaccines against nicotine, and some other targets. Further information about each of these and the market is available at http://www.nature.com/nrd/journal/v12/n2/full/nrd3914.html.
TNF Inhibition
A way to suppress persistent inflammation is one of the most important unmet needs we face in COPD. Inhibition of TNFα has been very successful in the management of several autoimmune diseases although, regretfully, it has not proved to be useful in addressing acute lung inflammation nor COPD, as a recent study showed (Citation1). However, TNFα is just one of a large superfamily of related cytokines. Inhibitors of many of these and their cognate receptors are in early development as potential treatments for inflammatory conditions such as COPD that may not be amenable to inhibitors of TNFα itself. Further information is available at http://www.nature.com/nrd/journal/v12/n2/pdf/nrd3930.pdf.
Bronchoscopic Lung Volume Reduction
In previous “Pipelines” I have reviewed some approaches to this issue, specifically valves and polymeric hydrogel sealant (Citation2) and the InterVapor System, and the PneumRx Coil (Citation3). Results of trials of the last 2 approaches to LVR have recently been published (Citation4, 5).
The InterVapor system uses superheated water vapor to create thermal injury in selected airways, -those that supply emphysematous lung regions. From a high-resolution CT, target regions are identified and a plan to navigate to those regions is made along with a computer-generated treatment program that determines the amount of thermal injury that will be delivered to each target airway. The rationale is that inflammation in the treated airways will result in their closure and consequent collapse of the relevant lung region thus reducing lung volume. In an uncontrolled study in 44 subjects with severe heterogeneous emphysema, clinically significant improvements were obtained at 6 months in FEV1, residual volumes, SGRQ (a mean reduction of 14 points), and 6 minute walk distance. The mMRC improved but only by 0.9 units (Citation4). The procedure was reportedly well tolerated, the commonest adverse event being “lower respiratory event,” which occurred in the first month. A more detailed description of the procedure is available http://www.uptakemedical.com/about-intervapor/how-it-works.
PneumRx Coil
This makes use of Nitinol (memory shape) metal coils that can be bronchoscopically positioned in emphysematous lung regions. Coils of varying lengths are delivered in their extended linear configuration into distal lung regions and anchored proximally. After placement, the coils tend to recover their pre-formed shape gathering up the diseased portions of lung thus reducing their volume. The process begins immediately. Ten or more coils can be placed at a single session which typically takes 30–60 min. Additional coils can be placed in subsequent sessions. Patients may report improvements in breathing and effort tolerance within hours.
A recent publication reports results in 28 patients (Citation5). Hemoptysis was common but described as mild. One patient experienced pneumothorax. Clinically meaningful improvements in mean FEV1, RV, SGRQ and 6MWT were reported and were maintained undiminished 6 months’ post-procedure.
Many of the methods that are now being employed to reduce lung volume are ineffective if there is inter-lobar collateral ventilation, a situation that is not easily detected even by high resolution CT. The Chartis System aims to provide information about this possibility. It consists of a catheter that can be bronchoscopically placed in potential target airways. A balloon close to the end of the catheter is inflated to occlude the airway and pressure and volume changes are measured and displayed on a console. If the pressure and flow do not change substantially when the airway is occluded, the lung region distal to the occlusion must have been supplied with collateral ventilation; the patient may not be a suitable candidate for a procedure such as the InterVapor system or placement of valves. A short video describes the Chartis system: http://www.pulmonx.com/animation-popup-chartis/index.html.
A MABA GSK436 and a Triple GSK and Theravance
GSK and Theravance have a MABA that has completed 7 trials through Phases I and II. A 4-week trial on 436 subjects has been published showing significant improvements in trough FEV1 in dose-related fashion and very few adverse events (Citation6). The agent is about to enter Phase III.
The same 2 companies have completed a Phase I trial of the above MABA and fluticasone propionate given separately or together versus each component (NCT 01449799). In terms of pharmacologic activity, this would be a triple combination, the first. Although GSK has 11 products for COPD in development, this ‘triple’ is not mentioned on their website. However, GSK does have another triple in development that is comprised of 3 discrete molecules, namely their own vilanterol, umeclidinium and fluticasone furoate. They also have 2 Phase III trials of their Advair plus umeclidinium (see www.clinicaltrials.gov). All of these employ GSK's Diskus dry powder delivery device.
Bimosiamose
Bimosiamose is a small-molecule pan-selectin antagonist being developed for its potential use as an anti-inflammatory agent in COPD, as I reported previously (Citation7). In in vitro studies it inhibited the attachment and ‘rolling’ of leukocytes to the vascular endothelium, preventing their diapedesis into extravascular tissues. It is being developed for asthma and Acute Lung Injury as well as COPD. The Phase II studies in 77 COPD subjects have just been published (Citation8). The trials were double-blind, cross-over, placebo-controlled in format, and subjects received the agent by inhalation twice daily by Akita nebulizer for 28 days. Usual bronchodilator therapy was permitted. Efficacy outcomes were induced sputum neutrophils, IL-8, MMP-9. And myeloperoxidase as well as lung function parameters. Bimosiamose treatment was associated with a significant reduction in sputum IL-8 and macrophage count but a non-significant change in sputum neutrophils. The drug was well tolerated.
Influenza Vaccines
The vaccine for the 2012–13 season was disappointingly ineffective, overall protection being 56%, with protection against influenza B being somewhat greater than against influenza A. However, among those aged 65 and older, namely half the COPD population, protection against influenza A was not significantly greater than zero. In addition, the rate of flu-related hospital admissions among 65-year-olds this winter was the highest on record.
Accordingly, more consistently effective vaccines are needed. Following a meeting of the Advisory Committee on Immunization Practices (ACIP), we are promised 4 new vaccines for next season. The new vaccines, all approved within the last year, are [quoting (Citation9)]
Flucelvax by Novartis — a trivalent, cell culture-based inactivated influenza vaccine (ccIIV3) approved for use in individuals 18 and older.
Flublok by Protein Sciences Corporation — a trivalent, recombinant hemagglutinin vaccine (RIV3) approved for use in adults ages 18 to 49
FluMist Quadrivalent by MedImmune — a quadrivalent LAIV approved for healthy, nonpregnant individuals ages 2 to 49 (all FluMist will protect against two A strains and two B strains for the upcoming season)
Fluarix Quadrivalent by GlaxoSmithKline — a quadrivalent, inactivated influenza vaccine (IIV4) approved for individuals ages 3 and older.
The ACIP deferred making specific recommendations among choices between these agents until a later date. That committee also reaffirmed its recommendation that all individuals 6 months and older receive flu vaccine.
Antisense RNA
Antisense RNA (asRNA) has long been known as a method of inhibiting the expression of an undesirable, e.g. mutated or over-expressed protein. In essence, asRNA is a single stranded oligo-RNA that is complementary to the mRNA of the protein whose expression is to be inhibited. Base pairing of the asRNA with mRNA converts the mRNA into double-stranded RNA which cannot be read at the ribosome. Difficulties with the application of this technology, particularly that of getting the intact asRNA molecule into the cell, abound. The first antisense oligonucleotide to be approved, fomiversen, was approved in 1998 but later withdrawn because of unanticipated problems.
The first second-generation asRNA, an apolipoprotein inhibitor called mipomersen, was FDA approved in January this year. Although this agent is not a treatment for COPD, it does constitute a ‘proof-of-concept’ that holds great promise for a whole range of chronic disorders including COPD. If basic research into the mechanisms of COPD inflammation were to reveal key pro-inflammatory proteins, the possibility of turning them off by antisense technology could be realized.
Acknowledgments
Some of the information found in this column was made available to the author through Citeline's Trial Trove ©. For more information on Trial Trove please visit www.citeline.com
References
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- Gross NJ. The COPD Pipeline COPD 2010; 7:154–156.
- Gross NJ. The COPD Pipeline XIX COPD; 9:649–650.
- Snell G, Bronchoscopic thermal vapour ablation therapy in the management of heterogeneous emphysema. Eur Respir J 2012; 39:1326–1333.
- Slebos D-J, Bronchoscopic lung volume reduction coil treatment of patients with severe heterogeneous emphysema. Chest 2012; 142:574–582.
- Pascal LML, A new class of bronchodilator improves lung function in COPD: A trial withGSK961081. ERJ Express February 21, 2013 as doi: 10.1183/09031936.00165712
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- Watz H, Inhaled pan-selectin antagonist bimosiamose attenuates airway inflammation in COPD. Pulm Pharmacol Therap 2013; 26:265–270.
- Jackson L, Interim adjusted estimates of seasonal influenza vaccine effectiveness—United States. February 2013 MMWR 2013; 62:119–123.