In previous COPD Pipeline columns I have tried to focus on novel molecules, entities, and devices. I have avoided “me-too” drugs, “line-extensions” and the like because, as specialists, we hear about these at annual meetings, clinical trial reports, etc. However, the field is becoming crowded with many very similar entities and their combinations. In an attempt to provide an overview (for myself as much as my reader colleagues), we review each of the major classes of COPD drugs and add brief comments about each entity and its stage of development. Inevitably, the review will be incomplete, for which we apologize.
We begin by looking at the market and sales for our present approved COPD drugs. We believe this will make it clear why there is so much interest in certain classes of agents. The website www.drugs.com provides a rank order of pharmaceutical products each year, http://www.drugs.com/ top200.html, from which the following table has been derived. By sales, the top 200 drugs for 2010 contain 11 agents that are used (but not necessarily FDA approved) for COPD; some are also used for asthma, of course. We do not include any antibiotics.
Ultra-long-acting beta-agonists (ULABAs)
The place of LABAs is well established in COPD practice and the guidelines, so almost every pharmaceutical company with a respiratory portfolio has one or is developing one, sometimes more than one. The expectation of any new LABA appears to be that it should be both quick-acting and have a duration of action of at least 24 hours. This would qualify it as a potential once-a-day drug, hence the designation Ultra-LABA. Concerns about LABA safety, although relevant mainly to their use in asthma, are leading to more extensive safety studies, even for drugs aiming for a COPD indication. The class was recently reviewed by Tashkin and Fabbri (Respir Res 2010;11:149), where additional features of each may be found. Beginning with those agents closest to approval, the Ultra-LABAs are:
Indacaterol.
A Novartis dry powder once-daily inhalation. Clinicaltrials.gov lists 41 studies including ongoing or recently completed phase I, II, III, and IV trials (the last being in Europe where it is approved as Onbrez Breezhaler. Its U.S. name will be Arcapta Neohaler). The agent is a potent bronchodilator with a rapid rate of onset and a trough FEV1 of 130–180 ml. Concerns about dosage temporarily delayed its approval in the United States, but while writing this, the approval of this agent by FDA was announced. The dose approved in the United States is 75 μgm, in other countries 150 and 300 μgm are approved. Indacaterol is also in trials in fixed combinations with antimuscarinic and corticosteroid drugs (later).
Olodaterol, BI-1744.
This BI agent has the rapid onset and prolonged duration of action of a desirable ULABA. The pivotal studies were done with 2 doses, 5 μg and 10 μg, and the drug will be delivered by the novel (to the US) delivery device, the Respimat, that provides what is called a “soft mist.” Very recently, questions have been raised about adverse events associated with the Respimat device (Singh S, et al BMJ 2011;342:d3215 doi 10.1136/bmj.3215). It is possible this will delay completion of this ULABA's development program.
Vilanterol trifenatate, GSK-642444.
A GlaxoSmithKline dry powder ULABA that is now in 10 simultaneous active COPD trials, many of them first listed early in 2011, including phase III studies and combinations with an anticholinergic or fluticasone fuorate. A single dose, 25 mg, is employed in each of the recent trials so evidently the phase II studies provided a clear indication of the appropriate dose. There is also a very active program with vilanterol in asthma, -an overall level that suggests the drug will come up soon for an NDA.
Carmoterol, CHF4226.
A Chiesi Farma product delivered by pMDI in 2 μg and 4 μg dosages. The duration of action was a concern to some uninvolved observers. Its future is unknown as no studies have been listed since 2 phase II studies were completed more than a year ago.
Milveterol, GSK-159797.
A GlaxoSmithKline dry powder LABA that was in 2 phase II asthma trials in Europe. As far as I can determine there has been no activity for at least 3 years so its future is unclear.
LAS-100977.
An Almirall LABA mentioned on that company's web site as a once-a-day agent that will be combined with an unspecified inhaled corticosteroid. The drug is not listed in any trials as either monotherapy or in a combination. The web site indicates an anticipated approval date of “>2014”.
PF-00610355.
A once-a-day Pfizer drug that has recently been in 2 phase II trials, one completed and the other fully enrolled but not completed. It's not clear whether its duration of activity persists for 24 h. The Pfizer Pipeline as of Feb 28, 2011 (http://www.pfizer.com/files/research/pipeline/2011_0228/ pipeline_2011_0228.pdf) shows 4 other Pfizer COPD agents in phases I or II which seem to be LABA's but for which I am unable to obtain any further information. It has been heard that Pfizer does not intend to build a respiratory portfolio.
AZD3199.
An AstraZeneca once-a-day dry powder. The latest trial is a phase II that began in October 2010 and competed early this year. No results available yet.
Long-acting anti-muscarinic agents (LAMAs)
Boehringer-Ingelheim's tiotropium bromide has been for some years the only LAMA in the COPD market. It is already an Ultra-LAMA. Its commercial success makes a new LAMA, if it were as good, very attractive to the pharmaceutical industry, so there are several in the pipeline. All successor molecules will be quaternary ammonium alkaloids, like ipra- and tiotropium, in order to take advantage of their poor systemic absorption when inhaled, thus minimizing the adverse effects seen with tertiary ammonium agents such as atropine itself. They will also be relatively specific antagonists of the M3 muscarinic receptor, sparing the M2 receptor. Tiotropium's slow onset of action is considered a weakness that will be exploited by competitors.
Tiotropium spiriva™
itself is to become available in an alternative formulation, by Respimat, the “soft mist” delivery device mentioned above. Besides being an alternative to the Handihaler™ device for patients who for whatever reason cannot or do not want to use the latter device, it is not clear what clinical advantage Respimat has over the Handihaler™ device. Because of the concerns referenced here, it is not clear when, or even if, it will become available in United States. It has been available in much of Europe for a few years.
Glycopyrronium, NVA 237.
A drug that was developed in the 1960s for a GI indication (and known as glycopyrrolate), the molecule has been off-patent for decades and intermittently considered for development as a bronchodilator, most recently by Sosei and Vectura. Now licensed to Novartis, it has been fairly intensively worked on by that company as a LAMA with a once-a-day potential. It has also been studied for a COPD indication as a pMDI by Chiesi (phase II) and Pearl's PT001 (phase II), and as a nebulized solution by Elevation (phase II). Novartis also aims to combine it with indacaterol in a fixed LABA-LAMA combination. It is also in studies for a variety of upper respiratory problems and for use in anesthesia, and for pediatric and neurologic uses. From all the information thus obtained, it has a good safety record. It has the potential advantage of having a somewhat more rapid rate of onset of action than tiotropium.
Aclidinium, LAS-34273.
A drug developed by Almirall with the collaboration of Forest, aclidinium has been in late stage development for some time. A dry powder formulation, if approved it will have the brand name Eklira® and be delivered by Almirall's Genuair® delivery device. Because there was uncertainty that it could be approved as a once-a-day agent, phase III studies of 2 doses, 200 and 400mg, in a twice daily schedule were completed and the drug has now (June 2011) been submitted as a b.i.d. drug for NDA.
GSK-573719
This is a GSK dry powder that first appeared in public in a phase I study in early 2007. Early this year, 2011, several phase III studies were initiated some in combination with GSK's LABA vilanterol. One deduces from this flurry of activity that 573719 received a strong go-ahead signal and will be positioned both to capture some of the Spiriva market and, in combination with GSK's LABA, to fill the need for a long-acting Combivent.
QAT370
A phase I trial of this Novartis LAMA has been performed(NCT00532350), but has not been mentioned again in clinicaltrials.gov or on Novartis's website
AZD8683
An AstraZeneca once-a-day dry powder agent that completed a phase IIa study in late 2010. No results available yet.
A review of recently issued patents for muscarinic antagonists for respiratory use was published in the June 2011 issue of Expert Opinion on Therapeutic Patents, an Informa Journal.
Fixed combinations
As with many other chronic diseases, combinations of agents with different and complimentary actions may provide better results for COPD patients than monotherapies. They are convenient and, in theory, improve the therapeutic ratio. A fixed combination of 2 drugs may also improve compliance leading to better outcomes, possibly decreasing costs. Combinations of an inhaled corticosteroid (ICS) and a LABA have been very successful in the cases of both Advair® and Symbicort®. Dulera® Merck-Schering-Plough's fixed combination of mometasone and formoterol in a MDI formulation has just entered the asthma field.
Again, many pharmaceutical companies want to share in the profits of such combinations, thus we have at least half a dozen similar combinations in trials presently. There may well soon be many more: with, say, 4 good ULABAs in late stages of development, and at least 4 good ICSs off patent or soon to be, there are conservatively 16 possible combinations of an ULABA and ICS with only minor differences among them. Indeed many pharmaceutical companies are working on the assumption that all COPD treatments for symptom relief will, in the near future, be combinations of long-acting agents, and that all monotherapies now in development should be considered transitional drugs that will find their long-term role almost entirely as components of fixed combinations. The approval of a monotherapy can thus be seen not as an end in itself, but as a necessary step to facilitate the regulatory process in the subsequent approval of a fixed combination of which that monotherapy is a component.
ICS/LABA combinations
Relovair, GW642444/GW685698.
GSK and Theravance are cosponsors of a fixed combination of vilanterol and the glucocorticoid, fluticasone fuorate. A phase II trial is listed in clinicaltrials.gov, but no changes have been noted since mid-2008 and its status is designated as “Unknown”. It is still listed on GSK's website pipeline in phase III for both COPD and asthma. One assumes it is still in active development.
Formoterol/mometasone dulera®.
A fixed combination MDI formulation being developed by Schering-Plough inherited by Merck following their merger. The combination was recently approved for an asthma indication and the expectation is that an NDA for COPD will follow shortly. It has been in 3 phase III COPD trials since 2006, but there do not seem to be any ongoing trials for a COPD indication at present.
Formoterol/fluticasone propionate.
A Dey/Mylan fixed combination in a nebulized formulation. Phase II studies have been completed and a phase III study is imminent.
Beclomethasone/formoterol, univair.
This is a fixed combination of 100 μg and 6 μg respectively being studied (phase III) by a group from University Hospital Antwerp with the collaboration of Chiesi Farma. It is not clear if there are plans to develop it as a commercial product. The co-primary outcomes suggest not, but naming the compound suggests it will be.
Beclomethasone/formoterol A.
Chiesi fixed combination HFA pMDI that has been in one phase III trial. There has been no activity since 2008, and the agent's status is given as “unknown” in clinicaltrials. gov
LABA/LAMA combinations
The only beta-agonist/anticholinergic combinations presently available are the albuterol/ipratropium combinations Combivent™, a pMDI, and Dey's DuoNeb™, a nebulizer solution, now generic. Both are successful products but of short duration. In the era of long-acting agents, a combination of two long-acting bronchodilators is seen as a logical extension. Thus there are at least 6 such agents in development
QVA-149 Indacaterol/glycopyrronium.
The Novartis product has received several phase III trials and must be near submission of an NDA.
BI-1744-CL/tiotropium.
As Boehringer-Ingelheim had great success with Combivent®, it is expected they would be quick to develop a long-acting version. Five trials, including 2 phase III trials and some employing the Respimat device had been completed by the end of 2010. Results have not been seen in a peer-reviewed publication as yet, but meeting abstracts suggest the combination will be very effective.
Vilanterol /GSK-573719
A GSK combination (mentioned above) in 10 trials including some long-term phase III studies.
Aclidinium/formoterol
An Almirall combination that has completed 2 phase II studies, the first as a once-a-day and the second, more recent trial as a b.i.d formu- lation.
Arformoterol/tiotropium
This combination is sponsored by Sunovion, the successor to Sepracor. In the phase IV trial (NCT00424528) that was completed in 2010, the two agents were given separately, not as a fixed combination. It is unclear and seems improbable whether this can or will be developed as a commercial product.
PT003.
This is a Pearl combination of glycopyrrolate and formoterol delivered as an aerosol. Several phase II studies are ongoing.
MABAs
A novel class of agents sometimes called bifunctional molecules, these are agents in which pairs of different classes of agent, pharmacophores, are joined together by a covalent link section. The pharmacophores are usually a beta agonist moiety and an antimuscarinic moiety, but other moieties with anti-inflammatory or PDE4i actions have been constructed. The first patents were issued in 2004.
GSK961081.
This is a joint venture of GSK and Theravance with beta-agonist and antimuscarinic activities, both of long duration according to the GSK website. The latest of 4 trials is an ongoing 28-day phase II study (NCT01319019). The drug is a DPI delivered by Diskus™. As an aside, part of the rationale for a MABA is that, as a single agent, it may simplify the path to regulatory approval; however, I understand it may still need to satisfy the “combination rule”, which is that each component must be shown to contribute to the efficacy of the combination. How does one do that with a single molecule? GSK and Theravance are using an inovative, although indirect, way. If I understand correctly, after the study agent, for example a MABA agent, has been administered and produced a level of response, a quick acting beta-agonist is administered to the subject to determine how much incremental bronchodilation can be obtained. That increment is, one assumes, due to available receptors not activated by the investigational MABA, and its magnitude is inversely related to the beta-agonism of the drug. The same procedure can be performed using ipratropium, yielding the same information for the anti-muscarinic moiety.
AstraZeneca/argenta.
They also had a MABA in preclinical a year ago, but it is no longer shown on their web site. Possibly it was shelved.
Triple combinations
Following the rationale that combinations simplify prescribing, convenience, and compliance of drug testing, some companies are taking it a step further and working on triple combinations. These consist of all our commonest classes, a beta agonist, an antimuscarinic and an inhaled corticosteroid. Obviously, the clinical development program and getting such an agent through regulatory approval will be challenging.
PT010
On its website, Pearl has one triple combination consisting of “corticosteroid + LABA + LAMA aerosol”. The identities of the components are not given but presumably are the glycopyrrolate and formoterol that Pearl has been working on. The triple combination has been in the preclinical stage for some time.
Boehringer-Ingelheim has one trial with a triple combination, including a “steroid”, tiotropium and salmeterol. It is in phase II (NCT00535366). No reports or results have been provided since 2008, and one is doubtful if its development will continue.
Phosphodiesterase 4 inhibitors (PDE4i's)
Now that roflumilast (Daliresp™), a Nycomed/Forest PDE4i, has been approved in the United States, other PDE4i's are back in development and may come up for approval in a few years.
Interest in these agents stemmed from the search for alternatives to theophylline when it was found that, in the dosages used in the 1980s, serious adverse events were associated with its use and were not uncommon. That theophylline had recently been found to be a PDE inhibitor and that PDE4 was the most abundant PDE subtype in the lungs, suggested the development of synthetic selective PDE4i's as alternatives to theophylline. In the 1990s there were probably at least a dozen potential PDE4i's in development. However, they all had, to some degree, the unfavorable GI effects of theophylline and, worse, questions about a possible mesenteric vasculitis. Because this imposed safety studies that were quite burdensome (repeated colonoscopies in at least one instance), and their potency as bronchodilators was not impressive, interest in these agents declined, and many were left on the shelf.
Roflumilast was one that had a good enough risk/benefit ratio to justify continued development, and its approval in 2010 reawakened interest in the class. Some candidate agents were taken back off the shelf and several new ones are being considered. Cilomilast (Ariflo™), probably the first to enter clinical trials in the late 1980's, was once turned down for FDA approval and seems not to be in development currently. Six other PDE4i's are known to be in development (the actual number is probably higher but their existence is unlikely to be publicized until they reach phase II).
GSK256066
This is an inhaled PDE4i (GlaxoSmithKline) in a completed phase II study (NCT00549679). This agent is also in trials for lung inflammation and allergic rhinitis.
Oglemilast, GRC-3886
This is a once-daily oral agent (Forest) drug has completed a phase II trial (NCT00671073). It is also in trials for asthma.
Tetomilast
OPC-6535 is an Otsuka Pharma once-daily oral PDE4i in two 24-month phase II trials (NCT00917150 and NCT00874497). Both trials will probably not complete until 2014.
Tofimilast
This is a dry powder inhaled PDE4i (Pfizer) that was in a phase II study (NCT00219622), but no developments have been announced since 2006, so it might have been laid to rest.
V11294
This is a PDE4D selective inhibitor that was in pre-clinical studies in the early 2000s (Gale DD, et al Pulm Pharmacol Ther 2003;16:97-104). It is not currently listed in clinicaltrials.gov.
HT0712
This is an oral PDE4i (Helicon Therapeutics) in phase I (NCT01215552). The trial was suspended reportedly to redesign the study as of May 2011.
PF-03715455 and PF-797804
These 2 agents are listed in the Respiratory section of Pfizer's Pipeline pages (http://www.pfizer.com/files/research/pipeline/2011_0228/ pipeline_2011_0228.pdf). Both are described as anti-inflammatory agents and could be PDE4i's. The first is an inhaled drug in phase I; the second is an oral agent in phase II.
ADC4022, inhaled theophylline
An interesting novel approach is the co-administration of budesonide and a low dose of theophylline by inhalation (NCT00634413). The rationale is based on the concept that theophylline stimulates histone deacetylase (HDAc), which restores or enhances the effect of a corticosteroid in COPD at the genome level. My understanding is that the HDAc effect is not related to PDE4 inhibition. A phase II trial has been completed. The development is sponsored by Pulmagen Therapeutics and Argenta is also involved.
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