Lung regeneration in COPD. In a previous “Pipeline” column I briefly reported on the use of Osiris's mesenchymal stem cells in COPD (COPD;2010:307–9). Since then, two reports introduce us to another approach to the use of stem cells to regenerate lung tissues. The first is a news report (not yet subjected to peer-review publication in a medical journal) of 2 patients with tracheal malignancies. To replace the tracheas, donor tracheas were stripped of their cells and repopulated with the recipients’ autologous stem cells derived from their nasal epithelium and bone marrow. The donor tracheal connective tissue became repopulated with the stem cells and the now reconstructed tracheas were used to replace the malignant tracheas. According to the report, the recipients were able to breathe, speak, and function within days <abcnews.go.com/Health/Health/successful-stem-cell …tr-ansplant/story?id…> The same group published a single case report in Lancet in 2008 where, using a similar approach, a donor trachea was used to replace a patient's left main bronchus. No immunosuppressants were used (Macchiarini P, et al., Lancet 2008;372:2023–2030). One would not make mention of a news report if it were not that a very similar approach has been carefully worked out and published in Science. Scientists at Yale stripped all cellular tissue from the lungs of rats. The acellular scaffold of airway, vascular and parenchymal connective tissue was then seeded with cultured epithelial and endothelial cells derived from rat stem cells. Remarkably, the seeded cells homed in to their appropriate stations on the connective tissue scaffold, repopulating it. The reconstituted and reimplanted organ was then able to support gas exchange for up to 2 hours (Petersen TH, et al., Science 2010;329:538–541).
The concept of replacing damaged, diseased organs with regenerated organs constituted from stem cells has been employed in other organs with growing success. The key seems to be to use a connective tissue scaffold derived from the appropriate organ and devoid of HLA antigen-expressing cells to act as a guide for autologous stem cells to seed the scaffold. Obviously, for regenerated lungs the clinic is a long way off. Huge problems remain to be solved, but this seems a plausible route to success.
The antibiotic gap. As I wrote in a previous “Pipeline”, the antibiotic field is a concern; the continuous need for new antibiotics is not being met. To judge by new antibiotic patents, the future looks problematic for clinicians such as pulmonologists who frequently use antibiotics. Annual growth of antibiotics over the last 5 years averaged 4%, as compared to more than 16% each for antivirals and vaccines. Only 5 new antibiotic molecular entities have been approved in the last 5 years, and only 2 truly novel classes of antibiotic have been introduced in the last 3 decades: oxazolidinone linezolid and the cyclic lipopeptide daptomycin. The reasons for this decline have to do mainly with marketing and are well reviewed by R. Hamad (Nature Reviews Drug Discovery 2010;9:675–6 I doi:10.1038/nrd3267). The current antibiotic pipeline consists of 52 known agents in discovery (the real number is probably many times larger), 152 agents in preclinical, and 28, 17, and 7 in Phases I, II, and III, respectively.
Five agents are in pre-registration at this time (September 2010). There are 2 cephalosporins, 2 glycopeptides, and 1 macrolide in late stage development. One of the cephalosporins, ceftobiprole (Basilea Pharmaceutica), is reported to be bactericidal for MRSA and Strep pneumoniae as well as other Gram negative and positive organisms. Another antibiotic in late stage is dalbavancin (Pfizer), a second-generation injectable glycopeptide also active against MRSA. Its very long half-life apparently gives it the potential to be the first once-weekly injectable antibiotic. Two other agents aimed at MRSA treatment in late stage are iclaprim and oritavancin.
An entirely new approach to MRSA is the discovery by researchers at Case Western Reserve that a protein, known as AgrA, is required for the release of MRSA toxins, and the activation of AgrA can be blocked chemically. This prevents the cascade of toxin release into the blood of an infected subject. The blockade of AgrA thus inhibits the toxicity of MRSA without killing it and, it is claimed, thus avoids the development of resistance http://www.dddmag.com/news-New-Drugs-Tame-MRSA-Toxicity-91710.aspx.
Absent from the pipeline are antibiotics for ventilator-associated pneumonia due to other organisms, K. pneumoniae and P. aeruginosa. Although there are also no new antibiotics for C.difficile in the pipeline, a need of the pulmonary community given how much broad spectrum antibiotics we use, the pipeline does contain monoclonal antibodies that target it (Extance A. Nature Rev. Drug Discov. 2010; 9, 177–178).
Adaptive Designs. A new tool for clinical trials. As we are only too well aware, clinical trials, particularly the large trials sponsored by government and pharmaceutical companies, have become demandingly complicated, slow to provide results and extremely expensive, but are essential if we are to practice evidence-based medicine. The development of Adaptive Design aims to address those problems by taking some well-designed shortcuts, but without sacrificing any of the rigor that is so essential for good science. In brief, adaptive design of a trial is a process by which a study can be modified at various prespecified times in prespecified ways based on interim analyses of the data.
The essence of “adaptiveness” is that it is entirely prospective. All the ways in which the study may be modified while it is in progress, including details of the protocol, sample size, treatment regimens, discontinuation or reassigning subjects, etc.—all must be anticipated and specified at the original protocol design stage. Usually, blindedness of all personnel other than specified data monitors is maintained. As ever, the FDA should be involved in the project during trial planning. The aim is to shorten the development process, get the drug or intervention to approval more rapidly and to achieve this result at a lower cost. It may also make better use of study subjects’ participation and shorten their exposure to ineffective or undesirable treatments wherever appropriate.
Clearly the Adaptive Design process of planning a trial will require much careful thought and imagination as one will essentially be planning multiple trials simultaneously. But, one's expectation is that we will very shortly be seeing more and more of these in the development of Pipeline drugs. Details of the requirements are provided in FDA's guidance document, http://www.fda.gov/downloads/Drugs/GuidanceComplian- ceRegulatoryInformation/Guidances/UCM201790.pdf Co- mmercial Adaptive Design software is being used in some industry trials, I have not reviewed any. The only link to the software I can find is http://www.linkedin.com/companies/ etrials-worldwide
The Status of the COPD Pipeline. It is a little more than a year since I first reviewed the landscape of drugs in development for COPD and respiratory disease in my December 2009 column. Biopharm Insight, the research organization that follows pharmaceutical companies and their activity, has again kindly provided me with their latest overall research data as of time of writing, September 2010. (Pharmaceutical research by academic and government entities and foundations is generally, but not always, included in their data).
There are a total of 32,786 investigational drugs in all stages of development from discovery, through NDA filing for regulatory approval. As there is essentially no requirement for an agent in development to be disclosed before it gets to Phase II, that number under-represents total research activity. A more reliable number, the total of investigational drugs in phases II through NDA filing, is 8,690 of which 262 (3.0%) are for a respiratory indication, and 79 (0.91%) are for the 4th leading cause of death in most of the developed world: COPD. Where does our research, respiratory diseases, stand in comparison with other therapeutic classes? Cancer is at the top, with 24.7% of the investigational drugs, followed in order by infectious diseases (12.2%), CNS (10.2%) and cardiovascular (6.7%). Respiratory is 12th. For the 79 COPD agents in phases II through NDA filing, 56 are in phase II, 18 in phase III, and 5 have been filed for NDA. At earlier stages there are 59 COPD drugs in ‘pre-clinical/discovery’ and 34 in phase I. A worldwide total of 97 pharmaceutical companies are working on these 172 agents. Again, there are certainly a lot more than the disclosed number of investigational drugs in early stages of development and many more companies working on them, mostly small biotech companies with just 1 or 2 agents.
What types of agents are being researched for COPD? It is not always possible to learn the mechanism of an investigational agent from public domain sources, particularly when the agent is in an early stage and when a pharmaceutical company is involved. My scan of the “mechanism of action” stated in some of the BioPharm Insight tables and many Pharma company websites suggests that the great majority of COPD drugs in development belong to classes of which we already have one or more approved members, e.g., LABAs, LAMAs, ICSs, combinations of these, generic versions, different formulations, etc. Also quite often, the ‘development’ is for an extended or refined indication of an existing approved drug; one suspects this has the primary purpose of extending the drug's patent protection. Apart from these, there are some new molecular entities (NMEs) that could represent real advances. For instance, there are a few PDE4 inhibitors, a few agents for pulmonary arterial hypertension, and, of most interest, some novel biologicals aimed at COPD inflammation.
How do these numbers compare with those I presented in late 2009? The total number of industry's investigational drugs has dipped about 9% as has the number of drugs aimed at a COPD indication. But the proportion of ‘Respiratory’ drugs to the total has also declined. We were in 11th place and are now in 12th, just ahead of “Dermatology”. Altogether, the numbers for COPD speak for themselves.
Clinicaltrials.gov offers another way of reviewing the pipeline. On September 20, 2010, the search term “COPD OR emphysema” yielded 1113 trials (this number includes many trials being partly or entirely conducted outside USA). Limiting the search to “open studies” (as opposed to “closed”) and “interventional” (as opposed to “observational”) and phases II and III one finds 85 studies as compared to 72 in 2009. Of these, Industry was the sole or principal sponsor of 51 trials (60%), as compared to 61% last time. As before, the proportion of trials supported by Industry was higher in the USA than in other countries. (The numbers from clinicaltrials.gov can be misleading for a number of reasons. Trials are not removed from the site when they close or when activity ceases, so the numbers always go up. There are many trials on the site that involve agents on which development has ceased altogether.)
Bimosiamose (Revotar Biopharmaceuticals). Revotar is a small German biotech company with a major interest in addressing chronic inflammation. Their lead product is bimosiamose, a small molecule that inhibits selectins. Selectins are the adhesion molecules that enable the attachment and “rolling” of leucocytes on the vascular endothelium, the first step in the neutrophil inflammatory response. Bimosiamose is taken daily by inhalation through a novel nebulizer device and is, or has been, in two phase II studies. NCT00962481 looked at the difference in absolute neutrophil cell counts in ozone-induced sputum between Bimosiamose and placebo treatment in smokers. The study has concluded with positive results. NCT01108913 is currently in progress and examines neutrophil counts and IL-8 in the sputum of patients with moderate COPD.
PA401 is the lead product of ProtAffin AG, a small biotech company in Austria that is developing “glycan-binding decoy proteins” using a “CellJammer® discovery technology”. PA401 is an IL-8 receptor antagonist that, in pre-clinical studies, has performed well in comparison with a PDE4i and the CXCR2 antagonist SCH527123, according to the company. Details were to be announced at the 2010 ERS meeting in Barcelona. (a press release following ERS Meeting states that results were very encouraging, http://www. protaffin.com/pressrelease/Protaffin_PA401_preclinical.pdf. A Phase I trial will be completed by the end of 2012)
Some once-a-day LABA-ICS combinations will come up for approval for COPD in the next year I believe. Relovair is a DPI fixed combination of fluticasone furoate and vilanterol trifenatate that has been through Phase IIB. A GSK-Theravance product, the trough FEV1 at the end of 28 days of maintenance treatment was 183ml above the placebo control : http://www.drugs.com/clinical_trials/gsk-theravance-ann- ounce-combination-ics-laba-phase-ii-results-relovair-development-programme-10155.html#ixzz10HIQ1PNj. Dulera® is Merck's fixed once-a-day HFA combination of mometasone furoate and formoterol that has been approved by FDA for adult asthma. Trials for a COPD indication are underway. Further along are 2 similar fixed combinations of mometasone furoate and formoterol that are being developed for a COPD indication by Novartis-Schering-Plough. Two Phase III trials have been completed, NCT00383721 and NCT00383435.
Biopharm Insight reports when the results of completed pharmaceutical sponsored clinical trials become available each month. For the month of July 2010, a total of approximately 150 studies with results were reported. For the month of August there were 125 studies. None of these were for a COPD indication.