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New medicines in development for COPD
Existing medicines provide control of the symptoms of COPD for many people. However, they do not halt or reverse the progress of disease, and there are some circumstances in which symptom control may not be adequate. There is therefore a substantial need for new medicines, and research into developing new therapies for COPD is intensive.
New medicines in current development address the needs of people with COPD through a variety of avenues:

Improved bronchodilators
Anti-inflammatory agents
Protease inhibitors.
Bronchodilators and their action on the airways
New treatments for stopping smoking

Better bronchodilators

Existing bronchodilators are effective in treating breathlessness, but such therapy can still be improved. At present, there are no once-daily beta-2 agonists available, and only one once-daily muscarinic antagonist. In addition, some people with COPD may find inhaled medicines difficult to use, but oral forms are limited to theophylline and some of the shorter-acting beta-2 agonists, which may provoke significant side effects throughout the body (tremor, headache, rapid heart rate, etc). There is thus a need for additional and improved bronchodilators, and research in this area is intensive.

New beta-2 agonists are under development by several companies:

Indacaterol (QAB149, Novartis) is in Phase 2 clinical trial as a once-a-day bronchodilator for COPD as well as asthma. An earlier study in people with mild-to-moderate COPD had shown that a bronchodilator effect is obtained within five minutes of dosing and persists for 24 hours, without significant effects on the heart, or on serum glucose or potassium levels, as may be observed with some older beta-2 agonists. Similar findings were recorded in another study in moderate-to-severe COPD.

GlaxoSmithKline also has inhaled, long-acting beta-2 agonists in clinical studies, with GSK159797, 159802, 597901, 642444 and 678007 at Phase 2.

In addition, Chiesi is investigating the inhaled once-daily beta-2 agonist carmoterol (CHF 4226), which has also reached Phase 2 development.

New muscarinic antagonists are also being developed.

Almirall has an inhaled long-acting once-daily anti-muscarinic (LAS34273) under Phase 3 development in COPD. This compound has been shown in a Phase 2 trial to have a bronchodilator effect with rapid onset that was sustained over 24 hours and maintained on repeated dosing, with few adverse effects.

Novartis has a candidate (NVA237) in Phase 2 trial, an inhaled form of a medication (glycopyrrolate) that has long been used for another purpose. It is selective for the M3 receptor in the lung, has a rapid onset of action and is effective over 24 hours. It is hoped that this can be developed as a oncedaily medication. Novartis has another muscarinic antagonist (QAT370) in Phase 1 study. It is also investigating the possibility of developing a fixed combination of NVA237 and its new beta-2 agonist indacaterol.

GlaxoSmithKline also has a number of new, long-acting muscarinic antagonists under study. The compound GSK233705 has reached Phase 2, while 656398 is at Phase 1. A substance that combines anti-muscarinic and beta-2 agonist activities in a single molecule (961081) is now at a preclinical stage of development.
In addition, certain compounds in other classes are being investigated for their potential effects on bronchoconstriction. Daiichi-Sankyo has the triple neurokinin antagonist CS-003 in Phase 2 trial and RottaPharms calcium-activated K+-channel opener Andolast has reached the same development stage in COPD.

Anti-inflammatory agents

Smoking-induced airways inflammation is characteristic of COPD and persists even after stopping smoking. Inhaled cigarette smoke acts on macrophages (cells of the immune system that constantly scavenge body systems such as the lung for harmful substances) and on the epithelial cells that line the airways, making them release cytokines (interleukin-1 beta, IL-; interleukin-8, IL-8; tissue necrosis factor alpha, TNF-?; leukotriene B4, LTB4; and others).

These cytokines, which are proteins secreted by cells of the immune system, attract other cells (monocytes, neutrophils, lymphocytes and more macrophages) out of the blood circulating through capillaries surrounding the alveoli and bronchioles and into the airways, where they interact and fuel the complex processes of inflammation.

Macrophages and neutrophils release substances (signalling cytokines and enzymes) that are closely involved in the disease process. Hence, damping down the inflammatory reaction in the airways might be expected to moderate and slow the progress of COPD.

Corticosteroids in current use do not reduce inflammation in COPD, as the neutrophils and macrophages responsible for prolonged inflammation are relatively resistant to their action. (Inhaled corticosteroids do, however, have other favourable effects on COPD, as noted earlier.) There is therefore a need for new steroids and other anti-inflammatory medicines that are effective in COPD, and a variety are being actively researched.

New steroids

New steroids in development include GlaxoSmithKlines 685698 and 799943 which are in Phase 2 study in combination with a longacting beta2-agonist. Also at Phase 2 are QAE 397 (Novartis) and TPI 1020, now in clinical study in the US by Topigen. TPI 1020 is based on the corticosteroid budesonide, which has been modified to have nitric oxide-donating actions. Nitric oxide relaxes smooth muscle, and TPI 1020 has been shown to be superior to budesonide in protecting against narrowing of the airways. It also inhibits migration of neutrophils into the lung and their subsequent activation.

Another new steroid, also in Phase 2 trials, is EPI-12323 (Epigenesis Pharmaceuticals). This does not bind to glucocorticoid receptors, and so has been found not to provoke the adverse effects associated with high doses of other steroids, such as Cushings syndrome, brittle bones, etc. In inhaled form, it has a long duration of action, making it suitable for once-a-day use.

Phosphodiesterase-4 inhibitors

Phosphodiesterases are enzymes that break down the cyclic nucleotides (c-AMP and c-GMP), which are key messengers that control many important processes in cells. One family of these enzymes, phosphodiesterase-4 (PDE4), has attracted particular interest in COPD, as it is the main type controlling c-AMP levels in neutrophils, monocytes and macrophages, and is also present in smooth muscle cells and epithelial cells, which are all central to the inflammatory response in COPD. If the activity of this enzyme could be inhibited, this might enable the inflammatory process to be turned down or off. PDE4 inhibitors have therefore been the focus of intense research activity.

Two PDE4 inhibitors are at an advanced stage of development cilomilast (GSK) and roflumilast (Altana). In a Phase 3 study in nearly 650 people with COPD, those given 24 weeks of treatment with dose of cilomilast twice daily were reported to show a significantly better trend in lung function (FEV1) than those who received placebo. They also showed a greater likelihood of being exacerbation-free during this time and had less breathlessness after exercise-testing than those taking placebo. In addition, there were improvements in their health-related quality of life. Some mild to moderate gastrointestinal side effects (nausea, diarrhoea, abdominal pain) were noted in 17 per cent of the cilomilast-treated group, as compared with eight per cent in the placebo group, but these were mainly recorded during the first three weeks of treatment.

The effect of oral roflumilast (taken once daily for 24 weeks) has also been investigated in a large Phase 3 study, giving a similar finding to that for cilomilast a more favourable trend in FEV1 over time compared with that in the placebo group and an improved health-related quality of life. The number of exacerbations was reported to be reduced at the higher dose of roflumilast. In this study, too, the number of gastrointestinal side effects decreased over time.

Both of these compounds have the potential to provoke gastrointestinal side effects. PDE4 not only occurs in cells in the lung, but is also present in cells in the brainstem. Following oral dosing, the concentration of PDE4 inhibitor in the circulation may be high enough to trigger nausea and vomiting in some people. An approach towards minimising such adverse effects would be to deliver the medication to the lung by inhalation (as with bronchodilators and steroids) and GSK has an inhaled PDE4 inhibitor (256066) in development, currently in Phase 1 trial.

Other companies are also developing PDE4 inhibitors. Ono has an oral compound (ONO- 6126) in Phase 2 study, as does Otsuka (tetomilast). Pfizers inhaled compound (tofimilast) is also at Phase 2, while Glenmarks oral inhibitor oglemilast has completed Phase 1 and is expected to start Phase 2 trials shortly in the United States.

Cytokine blockers

A large number of cytokines (proteins that affect cellular responses) are involved in inflammatory reactions and several approaches to treatment based on such targets may be possible.

Stopping the migration of monocytes and macrophages into the airways would be one way of damping down inflammation, and Novartis has a monoclonal antibody (ABN912) in Phase 1 studies that might have this effect. The company also has a monoclonal antibody (ACZ885) against Interleukin-1 at the same stage. IL-1 has been implicated in the collagen deposition that leads to the development of fibrosis of the airways (preventing their relaxation) which is an important aspect of advancing disease.

Blocking the action of key cytokines such as IL-8, TNF-? or LTB4 might be another way to reduce the inflammatory response. Boehringer Ingelheim has an LTB4 antagonist (amelubant) in Phase 2 study and AstraZeneca has a cytokine receptor antagonist of undeclared specificity at the Phase 1 stage (AZD 8309). An earlier trial of blocking TNF-? with a specific antibody (infliximab, Centocor) was, however, not successful, and it may be that blocking one cytokine alone is not enough to suppress inflammation.

Instead of blocking the action of cytokines, other compounds could be designed to inhibit their synthesis in response to an inflammatory stimulus (e.g. exposure to cigarette smoke). Preventing the expression of cytokine genes may block several inflammatory pathways simultaneously. One of the key regulators of inflammation is the enzyme p38 mitogenactivated protein kinase (p38 MAPK). This enzyme controls synthesis of IL-8, TNF-? and enzymes that are involved in tissue destruction in emphysema as well as in stimulating fibrosis. GSK has a p38 MAPK inhibitor (681323) in Phase 2 trial and another (856553) at Phase 1.

Protease inhibitors

Tissue destruction is a major feature of COPD. There is good evidence that an imbalance between naturally occurring proteases (which digest parts of the alveolar wall) and anti-proteases (such as alpha-1 anti-trypsin) that hold them in check is responsible for the tissue damage seen in emphysema. Neutrophil elastase, matrix metalloproteinases (MMPs) and cathepsins are some of the proteases released from activated neutrophils, macrophages and epithelial cells. Their destructive activity outweighs that of protective anti-proteases, leading to tissue damage.

Despite this clear disease mechanism, only a limited number of protease inhibitors are in development. AstraZeneca has one candidate compound (AZD 3342) in Phase 1 clinical trials and another in preclinical development (AZD 6067). Also, Ono has a neutrophil elastase inhibitor (ONO-6818) at the preclinical stage. In animal models, this was able to prevent changes typical of emphysema, such as airspace enlargement, loss of elastic recoil and lung hyperinflation.

Several new smoking cessation treatments are being actively explored. New oral medications designed to block the action of nicotine on brain reward centres are in development varenicline (Pfizer) and rimonabant and SSR 591813 (sanofi- aventis) as are three vaccines TA-NIC (Celtic Pharma), NicVAX (Nabi) and CYT002-NicQb (Cytos) - that stimulate the production of antibodies against nicotine that bind to it and prevent it passing into the brain.

Varenicline (Pfizer) is probably closest to being approved for use. An application for marketing authorisation was submitted to US and European regulators in November 2005. Varenicline binds to the same acetylcholine receptors in the brain as nicotine, and activates these receptors enough to reduce craving and withdrawal symptoms, while simultaneously blocking the action of nicotine at the receptors, reducing the satisfaction derived from smoking.

Rimonabant (sanofi-aventis) is another orally administered treatment being developed for stopping smoking. This compound, which has also been submitted for registration approval in the US and Europe, acts on different receptors in the brain from varenicline, but also aims to block the brains reward response to nicotine. Rimonabant acts on endocannabinoid (CB-1) receptors that are involved in nicotine dependence and the regulation of food intake.

In two ten-week studies, rimonabant produced significantly greater rates of stopping smoking than placebo. A third, one-year study showed that the compound was better able to sustain prolonged stopping than placebo. Those taking rimonabant lost a small amount of weight, whereas people given placebo gained a similar amount, presumably due to the effect of rimonabant on eating behaviour. Rimonabant was well tolerated in these studies, with nausea and upper respiratory tract infections being the main adverse events noted.
Three vaccines against nicotine are being developed: TA-NIC (Celtic Pharma), NicVAX (Nabi Biopharmaceuticals), and CYT002-NicQb (Cytos Biotechnology).

The TA-NIC vaccine consists of nicotine linked to genetically engineered (non-toxic) cholera toxin. A course of intramuscular injections causes the production of anti-nicotine antibodies, which bind nicotine entering the blood on smoking and prevent it crossing the blood-brain barrier. Preliminary results from a Phase 1 study in 60 smokers showed a significantly higher rate of stopping smoking among those given TA-NIC as compared with placebo (38 per cent stopped in the highest-dosed TA-NIC group, against 8 per cent in the placebo-treated group). This study was, however, designed to determine a suitable dose, not to establish efficacy, and the vaccine is now expected to enter a formal Phase 2 efficacy study.

A dose-ranging study has also been carried out for the NicVAX vaccine, which is being developed in the US. A tolerability and dose-finding study achieved similar rates to those found with TA-NIC (33 per cent in the highest-dosed group, versus 9 per cent in the placebo-treated group). This vaccine is also expected to enter a larger Phase 2 efficacy trial soon.
The third vaccine, CYT002-NicQb, has completed a Phase 2 trial in 341 healthy smokers, with follow-up for one year. Five injections of vaccine or placebo were given at monthly intervals. All of the participants treated with the vaccine developed anti-nicotine antibodies, although levels varied. In those with the highest antibody levels (high responders), 42 per cent were non-smokers throughout the entire period of weeks 8-52, which was significantly more than in the placebo group (21 per cent). The company has since established a dose level that should ensure that more than 80 per cent of participants in a planned Phase 3 study become high responders. Side effects (local injection site reactions, flu-like symptoms) were common, but mostly lasted less than 24 hours.


Posted on 09/19/08, 06:09 pm