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COPD Indication Report
December 22, 2005
Chronic obstructive pulmonary disease (COPD) is an inflammatory disease of the airways, primarily seen in people who have smoked. With 10.5 million diagnosed in the US, it is the fourth leading cause of death. Current treatments have centered around beta-agonist and anticholinergic medications that dilate the airways and corticosteroids that reduce inflammation. Combination products are commonly used, and inhaled products dominate the market. Many of the drugs are also used to treat asthma. Advair, a combination of a long-acting beta-agonist and corticosteroid, is the leader in terms of sales. Spiriva, a long-acting anticholinergic, was recently introduced and is gaining popularity. We believe it will dominate the anticholinergics in the near term, and continue to grow that segment.
While there is a need for new agents to combat the basic disease process of COPD, there are few in development. Ariflo and Daxas are phosphodiesterase inhibitors that reduce inflammation. Because of its limited efficacy, we are doubtful about the prospects for Ariflo, which has received an approvable letter. Daxas has had better results, but these have not been stellar, and we think its market penetration will be limited. Other drugs in development are aimed at making existing types of treatment more effective or convenient. There are several beta-agonist/inhaled corticosteroid combinations on the horizon poised to challenge Advair. We think Symbicort and Flutiform, which contain a long-acting beta-agonist with a faster onset of action, will gain significant minority shares in COPD, but the market will later be dominated by once-a-day formulations, such as a GSK159797-inhaled steroid combination. In addition, a generic version of Advair is likely to arise and take a sizeable share. A combination of a long-acting anticholinergic and beta-agonist, such as NVA237/QAB149, is likely to do well in the anticholinergic segment, though we think it is unlikely to displace the beta-agonist/inhaled corticosteroids.
BACKGROUND
According to the Centers for Disease Control, in 2000, 10.5 million people in the US were diagnosed with chronic obstructive pulmonary disease (COPD). COPD is the fourth leading cause of death in the US and Europe.
COPD is an inflammatory disease of the airways, caused by an abnormal response of the lungs to noxious particles or gases, primarily from cigarette smoking (80-90% of cases). The hallmark of COPD is an airflow limitation that is not fully reversible. Though the disease has a variable course, a general time course is: smoking begins during youth, lung function decline becomes apparent when smokers reach age 40-50 years, hospitalizations begin when smokers reach age 50-69, and deaths occur when they reach age 60-79 (Centers for Disease Control). If smoking is stopped, there can be some improvement and stabilizing of lung function, though the disease may still continue to progress due to the normal decline in lung function seen with aging.
The predominant forms of COPD are chronic bronchitis and emphysema, though in a given patient the relative contribution of each is often difficult to discern. Chronic bronchitis, which is more common, is a condition where the irritated, inflamed airways produce thick mucus that obstructs air flow. In emphysema, there is destruction of the walls of the air sacs of the lungs.
Symptoms of COPD include cough, sputum production, wheezing, and shortness of breath. COPD must be distinguished from asthma, a condition that also involves inflammation and airflow obstruction. In asthma, the airways greatly constrict in response to a variety of inhaled irritants, the airflow obstruction is very reversible (with medications called bronchodilators, which relax the muscles around the airways), and the pattern of inflammation is different. In many cases, asthma and COPD can be difficult to distinguish or may co-exist. Most COPD patients have some degree of reversibility of airway constriction. American Thoracic Society (ATS)/European Respirator Society (ERS) joint guidelines suggest that for practical purposes, treatment for patients in whom asthma and COPD cannot be distinguished should be similar to that of asthma.
The diagnosis of COPD requires a test called spirometry, in which a patient exhales rapidly into a tube. The most significant measurements are the total amount of air forcefully exhaled (FVC: forced vital capacity) and the amount exhaled after 1 second (FEV1: Forced Expiratory Volume in 1 second). The test is performed after giving the patient a bronchodilator, to minimize any reversible airway constriction. If the FEV1/FVC (the amount exhaled after 1 second divided by the total) after exposure to the bronchodilator is less than 0.7, the test indicates airway obstruction that is not reversible and hence consistent with COPD.
The severity of COPD can also be classified by spirometry testing:
| Severity |
Postbronchodilator FEV1/FVC |
FEV1 % of expected for a normal individual | |
|
At risk
Patients
who: -smoke or have exposure to pollutants -have cough, sputum or dyspnea -have a family history of respiratory disease |
>0.7 | =80 | |
| Mild COPD | =0.7 | =80 | |
| Moderate COPD | =0.7 | 50–80 | |
| Severe COPD | =0.7 | 30–50 | |
| Very severe COPD | =0.7 | <30 | |
|
|||
While the FEV1 test is a standard test to assess function, it does not always correlate with a patient’s condition: small changes in FEV1 with treatment can be associated with good improvement in symptoms and functioning.
Other measures of severity of disease are symptom scales that reflect the difficulty patients have with breathing after various activities.
CURRENT TREATMENT
Current treatment is aimed at reducing symptoms and improving respiratory ability, but outside of quitting smoking, no current treatment has been shown to reduce the overall decline in lung function seen with COPD. When available, inhaled medications are preferred because smaller doses can be used to achieve similar or greater efficacy, with fewer side effects.
Inhaler Devices
The most commonly used delivery devices for inhaled products are metered dose inhalers (MDIs) or dry powder inhalers (DPI). These are small, portable devices. MDIs are the traditional aerosol devices that require coordinating a breath with spraying the aerosol, though breath-activated devices are also available now. In DPIs, the drug is only inhaled when a breath is taken. However, patients must take more forceful breaths than with an MDI, since there is no aerosol propellant.
If used properly, MDIs are as effective as DPIs. Using a spacer, essentially a chamber into which the aerosol is sprayed, makes use of MDIs easier and also reduces deposition of the drug in the mouth and upper airways. This is particularly important when using inhaled steroids to reduce oral side effects. Another issue with MDIs is that they have traditionally used chlorofluorocarbon (CFC) propellants. The FDA has ruled that single agent albuterol inhalers (see below), the most commonly used inhalers with CFCs, must be phased out by December 31, 2008 due to environmental concerns. There are already alternatives on the market designated HFA for their use of a hydrofluoroalkane propellant (patents on these products extend through 2010-2017). The HFA formulations are more effective than MDIs or DPIs in reaching the lung.
Nebulizers, which create a mist from liquid formulations, are not recommended for long-term use, but rather for exacerbations. In addition to being less convenient, cost is a limiting factor. In practice, some patients do use them for regular treatment, particularly since they are becoming more convenient and portable. However, they still represent a minority of the market.
This report focuses on non-nebulized inhaled drugs and novel oral ones.
Treatment Regimens
The mainstays of COPD pharmacotherapy are bronchodilators (which open up the airways by causing smooth muscles around the airways to relax) and glucocorticoids (which reduce inflammation). The bronchodilators include:
- Beta-agonists: mostly inhaled drugs that preferentially dilate the smaller airway by stimulating beta 2 adrenergic receptors. They may be short (< 6 hours) or long (>12 hours) acting.
- Anticholinergics: inhaled drugs that dilate larger airways by blocking muscarinic acetylcholine receptors. They also diminish mucous secretion. They too may be short or long-acting.
- Methylxanthines: oral agents that block an enzyme called phosphodiesterase. Because the doses of oral methylxanthines needed for bronchodilation are high enough that there is also a significant risk of increasing toxicity, some guidelines recommend them only if inhaled bronchodilators are not sufficient. As they are used in a minority of patients, they are not covered in this report.
For stable COPD, the table below shows recommended pharmacologic treatment for various stages (adapted from the Global Initiative for Chronic Obstructive Lung Disease guidelines):
| Mild | Moderate | Severe | Very Severe |
| Add short-acting bronchodilator as needed. | |||
| Add regular treatment with one or more long-acting bronchodilators. (If one class is not effective, an alternate one may be used.) | |||
| Add inhaled glucocorticosteroids if repeated exacerbations | |||
There are some differences between what is recommended in guidelines and the way stable COPD is actually treated. Though inhaled steroids have only demonstrated a clear benefit in more severe cases in studies of COPD, they are also used to a significant extent in patients with less severe disease (perhaps because a number of patients have reversible airway constriction and may have an asthmatic component; in asthma, inhaled corticosteroids are recommended as first-line treatment). Also, since until recently a long-acting anticholinergic was not available in the US (Spiriva, see below), short-term anticholinergics have been used as maintenance medications.
Exacerbations of COPD are treated on an outpatient, emergency room, or inpatient basis depending on the severity. Treatment begins with increasing the dose or frequency of inhaled bronchodilators with short-acting agents. Short-term high-dose nebulizer treatment with these medications is used in severe cases. A long-acting bronchodilator can be added if the patient is not using one already, as well as inhaled corticosteroids. Oral or intravenous corticosteroids are used in patients with severe COPD and those requiring hospitalization. Antibiotics are used if an infection is suspected.
The following are current brands of inhaled bronchodilators and steroids along with their formulations in the US:
| Anticholinergics | Beta-agonists | Steroids** | ||
| Long-acting | Short-acting |
Short-acting (SABA) |
Long-acting (LABA) |
|
|
Tiotropium (Spiriva DPI) |
Ipratropium (Atrovent MDI, HFA) |
Albuterol-Salbutamol (Proventil MDI, HFA, Ventolin MDI, HFA, generics MDI, HFA*)
Metaproterenol
Pirbuterol
Levalbuterol |
Formoterol (Foradil DPI)
Salmeterol |
Beclomethasone (Qvar HFA)
Budesonide
Fluticasone***
Flunisolide
Triamcinolone |
|
Combinations: |
||||
|
Ipratropium/Albuterol (Combivent MDI) |
Salmeterol/Fluticasone (Advair DPI) |
|||
*One generic albuterol HFA available from IVAX.
**The inhaled corticosteroids are commonly used, but not approved for COPD.
***A Flovent DPI is approved (Discus) but not yet being sold in US.
Short-acting Inhaled Bronchodilators
Short-acting inhaled bronchodilators are recommended alone for as needed use in patients with mild disease, or as additional treatment as needed in conjunction with long-acting bronchodilators in patients with moderate or severe disease. (They are also used preventatively before situations likely to provoke symptoms.)
Due to their quick onset of action and brief duration, short-acting beta-agonists are the best suited medications for as needed use, and are the most widely sold inhaled drug. While this segment has been dominated by generically available albuterol, the above-mentioned ban on CFC propellants, to take place by December 31, 2008, will change the competitive landscape. To date, there are two branded formulations of albuterol with the new HFA propellant (Proventil- Schering-Plough and Ventolin- GlaxoSmithKline) and one generic (from IVAX). These are generally priced $20 or more over the CFC generics. It is unclear whether 3M Corporation, which holds the HFA patents, will license the technology for more generic albuterol HFA competition.
Xopenex (Sepracor, Abbott) is a novel short-acting beta-agonist: the R enantiomer of albuterol (albuterol is a mix of two enantiomers: molecules that have the same chemical makeup but are mirror images of each other). An HFA formulation was approved in March 2005 for “reversible bronchospasm,” but due to manufacturing issues the drug only became available in December 2005. The rationale for Xopenex is that the R enantiomer is the more active form, and there are some concerns that the S enantiomer may have proinflammatory effects. We have not seen data for the HFA formulation in COPD. Sepracor’s nebulized Xopenex has shown mixed results in COPD: it has not shown significant improvements in pulmonary function over standard treatment, but in one study, it led to fewer withdrawals due to exacerbations than regular albuterol. A retrospective study showed the nebulized version used in a hospital led to a shorter length of stay, fewer rescue medications, and fewer readmissions than regular albuterol. For the HFA version used in asthma, pulmonary function is similar to equivalent doses of albuterol HFA. Without more data showing an outcomes benefit, we do not think there will be a compelling clinical argument in favor of Xopenex HFA for COPD, though its theoretical advantage and the benefit seen with the nebulized form is likely to help it. For more on Xopenex HFA and the CFC ban, please see the market summary below.
Compared to short-acting beta-agonists, short-acting anticholinergics are more potent at regular doses in COPD. Anticholinergics are more effective in COPD than in asthma, and hence are commonly used in COPD. The short-acting anticholinergics have a slower onset of action (20-30 minutes vs 1-3 minutes) and longer duration than the beta-agonists, making them less suitable for as needed use. Nevertheless, they are recommended in guidelines, and a number of physicians do prescribe them for as needed use, particularly since some patients may respond better to anticholinergics than beta-agonists. For example, in one study, 35% of COPD patients showed an improvement in FEV1 with either beta-agonists or anticholinergics, 27% responded to albuterol alone, and 11% responded to the anticholinergic Atrovent (Boehringer Ingelheim) alone. (Atrovent is the sole single-agent anticholinergic for use in a portable inhaler in the US.) As noted above, since a long-acting anticholinergic was only recently introduced in the US, short-acting anticholinergics have also been used for maintenance treatment.
Anticholinergics can be used alone or in combination with beta-agonists, corticosteroids (for patients with frequent exacerbations), or both. Currently, the most commonly used anticholinergic is a combination medication called Combivent (Boehringer Ingelheim), which includes albuterol and the active ingredient of Atrovent. The combination has been shown to work better than either component alone (an improvement in FEV1 for single agents of about 25% versus 32% for the combination) and of course is more convenient. As a result, Combivent is prescribed about 4 times more than Atrovent. Its major disadvantage is its short duration of action: the usual dosage is 2 puffs 4 times a day. Though it has a comparative price advantage, this makes it vulnerable to longer-acting medications, such as Spiriva (see below), launched in 2004.
Long-acting Inhaled Bronchodilators
The long-acting inhaled bronchodilators are recommended for maintenance treatment of patients with persistent symptoms, usually moderate or severe disease. If an agent is insufficient, it can be switched or combined with one that has a different mechanism of action.
Serevent (GlaxoSmithKline) is the oldest long-acting inhaled bronchodilator in the US, approved for asthma in 1994 and for COPD in 1998. It is given twice daily. The active part of the molecule is the same as for albuterol. Studies have not shown dramatic benefits with Serevent use over other treatment, though there is some evidence for a reduction in COPD exacerbations compared to Atrovent (20.7% vs 30.8% of patients having their first exacerbation in 12 weeks). In asthma, Serevent had negative publicity arising out of the SMART trial (Salmeterol Multi-center Asthma Research Trial), where adding Serevent to usual treatment resulted in a small but significant increase in mortality. (There was no increase, however, in patients also receiving corticosteroids.) That led to a black-box warning in 2003. More recently, on November 18, 2005, the FDA requested changes in the label for Serevent, as well as Foradil and Advair (see below), recommending that these agents only be used for asthma patients failing corticosteroids. Thus far, the concern has not extended to COPD patients, and guidelines have not changed recommendations that in COPD these agents be used before corticosteroids. In COPD the long-acting beta-agonists have not been seen to worsen exacerbations, as they have in asthma. Nevertheless, the warning may raise concern over patients with an asthmatic component to their disease. The patent on the active ingredient of Serevent is due to expire in 2008 in the USA and 2005 in most of Europe.
Competitor Foradil (Schering-Plough, Novartis, Astellas), approved in 2001 in the US, has a faster onset of action than Serevent, but in direct comparisons of stable doses, this has not been shown to translate into a definite clinical advantage, with the exception of earlier improvements in FEV1. Like Serevent, Foradil is given twice daily and has also shown some evidence of a clinical benefit above Atrovent. Foradil has been hampered because the device is less convenient to use: unlike Serevent, blisters containing the medication must be put into the device one at a time. The US patent for Foradil’s active ingredient is set to expire in February 2006, and has expired in other major countries. Another competitor with the same active ingredient, Oxis (AstraZeneca), is available in Europe, where a generic version has also appeared.
Despite the fact that they are recommended as initial maintenance therapy for COPD, market share for these LABAs is relatively low, due to competition from Advair (see below), a combination product.
Spiriva (Pfizer, Boehringer Ingelheim) is the sole long-acting anti-cholinergic agent, approved in the US in January 2004. It is approved only for COPD, not for asthma. Unlike the other currently approved long-acting bronchodilators, it is given once-a-day. Spiriva has shown improvements in lung function greater than Serevent, and in a comparative trial had a numerically greater reduction in exacerbations (the difference between Spiriva and placebo was statistically significant, whereas that between Serevent and placebo was not). The only adverse event significantly worse with Spiriva was dry mouth (8.2% vs 1.7% Serevent). Spiriva has shown better symptom control than Atrovent, and there is preliminary evidence it may slow the decline in FEV1. A large trial (UPLIFT) to better evaluate Spiriva’s ability to slow progression of COPD completed enrollment in March 2004, with results expected in 2008. As noted above, to date no treatment (other than smoking cessation) has been shown to reduce progression.
At this year’s European Respiratory Society meeting, data from a 6-week trial was presented showing greater changes in various measures of FEV1 for Spiriva plus Foradil versus a free combination of Serevent plus the corticosteroid Flovent. This study was aimed at competitor Advair. However, the results are not entirely unexpected, since the Spiriva-Foradil combination involved two bronchodilators. We will speak more about this and Spiriva’s competitive position in the market summary below.
Inhaled Corticosteroids (ICS)
Glucocorticoids act at a number of levels to reduce inflammation. These include reducing the number and availability of inflammatory cells and inhibiting the production and release of chemicals that mediate the inflammatory response. Due to their numerous side effects in the body, oral corticosteroids are only used for short periods to treat exacerbations of COPD. ICSs, on the other hand, are generally thought to be safe for long-term use, though one large study has shown a decline in bone density and an increased risk of bruising.
As noted above, in COPD, ICSs are recommended only after failure of bronchodilators, though in practice they are commonly used earlier on. Also, single agent ICSs have not actually been approved for COPD, but are used nonetheless.
Pharmacological properties of different ICSs influence how effective they are in the respiratory system and the degree of systemic side effects. For example, particle size and formulation influences how much gets to the lung after an inhaled dose and how much is deposited in the mouth, where it can be swallowed and potentially have a systemic effect. Even if a drug is swallowed, if it is metabolized to a high degree in the liver (resulting in what is called low bioavailability), it will also have less systemic absorption. Products that dissolve better in lipid solutions (lipophilicity) than in water are thought to have a more prolonged action in the lung.
Due to their advantage in factors such as these, Flovent (GlaxoSmithKline) and Pulmicort (AstraZeneca) are the most commonly used single agents (Pulmicort is commonly used as a nebulized formulation). In addition, the active ingredient of Flovent is used in Advair, and the active ingredient of Pulmicort is being developed as a combination product with the long-acting beta-agonist formoterol (see Symbicort below).
An ICS may be used in a fixed combination for convenience (Advair is the only combination currently available in the US), or alone, when they are to be used with a bronchodilator other than the one in Advair or when more flexible dosing is required.
LABA/ICS Combination
Advair (GlaxoSmithKline) is a combination of salmeterol (the active ingredient of the LABA Serevent) and fluticasone (the active ingredient of the ICS Flovent). Advair has shown significant effects on pulmonary function and symptoms beyond those compared to either component alone, without significantly increasing side effects. While Advair has demonstrated numerically lower rates of exacerbations than its components, the results have not been statistically significant. As expected from its ICS component, the largest benefit for Advair in reducing exacerbations is in severe disease, but it is commonly used earlier on, as well.
An uncontrolled study has suggested that use of both individual components in Advair treatment reduces mortality compared to patients who do not use a steroid or long-acting beta-agonist. A large three-year study (TORCH) evaluating this for Advair, its components, and placebo is currently underway and results are expected in 2006. In addition, when Advair was approved for COPD, GSK had committed to further studies on Advair’s effects on COPD exacerbations and bone mineral density. The final reports for these are due in August and December 2007.
The clinical benefits and convenience of Advair has propelled it to the best selling (in terms of revenue) inhaled pulmonary drug, with US and worldwide sales of $2.4 billion and $4.5 billion respectively in 2004. An estimated 30% of the sales are due to COPD. GSK’s patent on the specific combination of active ingredients in Advair expires in 2010 in the US and 2013 in Europe. While there may be more difficulties in developing generic inhaled combination products compared to oral ones, we believe the market is so large that a generic substitute for Advair will arise.
Current Market Summary
For as needed medications, albuterol is the market leader, though sales figures are not high due to generics. Revenues are likely to increase significantly after 2008 when the CFC bearing generics are banned. Unless 3M grants more licenses for generic albuterol HFA, this is likely to last until between 2010 to 2017, depending on which patents for the HFA formulations are deemed valid. Without more data showing a benefit, Xopenex HFA is unlikely to gain significant share until the CFC ban, after which we believe it will have modest penetration, but lose share again when generic HFA formulation enter. Since the anticholinergics are priced above the HFA albuterol formulations, the switch to HFA is unlikely to affect anticholinergic as needed usage.
For maintenance bronchodilators, Advair is by far the best selling. It offers a combination of a bronchodilator and a steroid to fight inflammation and as a result is much more popular than the single long-acting beta-agonists, Serevent and Foradil. Single agent corticosteroids are used about 50-60% as much as Advair. The anticholinergics are also commonly used, with Combivent currently the most prescribed. Atrovent and Combivent are likely used alone as maintenance medications in less severe patients, or together with Advair (or Combivent plus an ICS) in more severe patients. Spiriva has shown strong growth since its introduction, and we believe that due to its convenience and efficacy, it will increasingly erode Atrovent and Combivent share. For example, we think Spiriva plus Advair will generally be preferred over Combivent plus a steroid for patients with more severe disease. Spiriva is also likely to expand the anticholinergic segment somewhat, for example in combination with Advair in patients who did not want to use the short-acting anticholinergics, in place of LABAs, or inducing more patients on as needed albuterol to use Spiriva as a maintenance medication.
Spiriva’s superiority over Serevent, along with the study showing greater improvement in lung function for Spiriva plus Foradil compared to the components of Advair, raises questions about whether Spiriva alone or with a beta-agonist should be used instead of Advair, particularly in patients with less severe disease. This is certainly more in line with guidelines, which recommend steroid use only in severe COPD. But while we think Spiriva will take some share from Advair in new patients with less severe disease, we believe that for many patients, physicians will view the corticosteroid component as important, and the impact on Advair will be relatively small.
Existing treatment leaves a great need for drugs that alter the basic inflammatory process of COPD. However, with only a couple exceptions, most drugs in late stage development are attempts at improving existing treatment. Particularly since compliance is a big problem in COPD, one trend is the development of inhaled drugs dosed once-a-day.
DRUGS IN DEVELOPMENT
DRUGS IN NDA
Foradil Certihaler - Schering-Plough (SGP), Novartis (NVS), SkyePharma (SKYE)
Foradil Certihaler is a multidose dry powder formulation of Foradil Aerolizer, which is a single dose DPI. Hence the advantage of the new formulation is convenience of the multi-dose feature. While it is likely to do better than and take share from Foradil (and Serevent), we believe the single agent LABAs have limited market potential.
Arformoterol – Sepracor (SEPR) and Novartis (NVS)
Arformoterol is a single enantiomer form of the active ingredient of Foradil, being developed as the first nebulized long-acting beta-agonist. As mentioned above, enantiomers are mirror image molecules. Normally, formulations include both molecules. The NDA was submitted on December 13, 2005. Sepracor has completed two phase III studies and a chronic safety study. There is little comparative clinical information on the drug, but we think it is likely to be approved for the more limited nebulizer market.
DRUGS IN PHASE III DEVELOPMENT
Asmanex - Schering-Plough (SGP)
Asmanex is a long-acting DPI corticosteroid, which unlike current formulations is usually dosed once-a-day. It is already approved for use in asthma (in March 2005), and was launched late in the third quarter. Of approved ICSs, Asmanex has the highest affinity for the corticosteroid receptor. It has a number of pharmacologic properties thought to reduce systemic effects, though it shares these with other competitors. Its major point of differentiation is convenience.
Despite its convenience, we think without showing a more pronounced clinical benefit, uptake will be slow in competition against established drugs. It is unlikely to affect the share of market leader Advair, unless it is formulated into a combination with a once-a-day bronchodilator. A combination of Asmanex and the LABA Foradil (Novartis, Schering-Plough, Astellas) is in phase I development for COPD and phase II for asthma. We have doubts about whether this medicine will provide any benefit above current treatment, however, as Foradil requires twice-a-day dosing.
Symbicort is a combination of the long-acting bronchodilator formoterol (the active ingredient in Foradil and Oxis - the latter is AZN’s drug) and budesonide (the active ingredient in Pulmicort). It is a twice daily formulation, being developed for an MDI in the US (according to AstraZeneca, the Turbohaler DPI formulation is not being developed in the US due to the regulatory burden regarding manufacturing issues). Currently, an NDA was submitted in September 2005 for asthma, and it is in phase III development for COPD. It is already approved in Europe, and we think approval in the US is likely, though there have been manufacturing issues. (Patents are due to expire 2012 in most major European countries, and approximately in 2014 in the US.) Symbicort has been shown to reduce exacerbations beyond formoterol alone and improve lung function beyond budesonide alone. It is a direct competitor for Advair. There have not been adequate trials comparing Symbicort with Advair in COPD, though the faster onset of Symbicort’s LABA is likely to be an advantage. On the other hand, if swallowed the corticosteroid in Symbicort has a greater likelihood of reaching the circulation and causing systemic effects.
In asthma, AstraZeneca has been supporting flexible dosing of Symbicort, where patients use baseline Symbicort and increase usage as needed (instead of adding short-acting agents). Symbicort is more suitable for this than Advair, because of the faster onset of action of the beta-agonist in Symbicort. While this may help Symbicort gain an advantage in asthma, the concept of flexible dosing has less relevance to COPD, where there is less of a reversible component. On the other hand, patients with COPD have a low compliance in medication usage (< 50% in one study), suggesting they may use their medications to some extent on a more as-needed basis anyways. As a result, some patients may prefer Symbicort. In addition, physicians typically prescribing Symbicort for their asthma patients are also likely to use it for their COPD patients. AstraZeneca has not disclosed whether the US submission for the MDI formulation is for fixed or flexible dosing.
We believe Symbicort will be used off-label for COPD after approved for asthma, and is likely to be approved for COPD, as well. While we think that it will gain a healthy share, due to its late entrance and lack of a dramatic clinical superiority, we do not think it will engender across-the-board switching in patients using Advair for COPD.
Alvesco – Altana (AAA) and Sanofi-Aventis (SNY)
Alvesco is a once-a-day corticosteroid (twice-a-day for high doses) in phase III development for asthma. It is delivered by an HFA MDI. We include it in our analysis, as many of the existing steroids used in COPD have only been approved for asthma. Alvesco is a prodrug that is activated in the lungs. It scores high on the list of pharmacologic properties of a desired ICS. In addition to convenience, a significant advantage is a lower incidence of oral fungal infections, a side effect of corticosteroid deposition in the mouth. However, of concern was a study of high doses showing an increased rate of cataracts with high dose Alvesco (2.4% for Alvesco 160 microgram twice-a-day; 6.2% for Alvesco 320 micrograms twice-a-day, 0.7% for Flovent 440 micrograms twice-a-day, and 0.7% for placebo).
Alvesco received an FDA approvable letter in 2004, but further clinical information was needed. One trial evaluating the eye effects of Alvesco has already been completed. While the company has stated it showed good safety, the data have not yet been released. Two additional trials, 12 week and 16 week studies looking at once-a-day versus twice-a-day dosing, were instituted this year and are slated to be finished August 2006. Alvesco was approved in the first European country in April 2004, but only for the lower dosages of the drug.
Despite company reassurances, we are concerned that the high dosages do lead to a higher rate of cataracts and will not be approved in the US either. That means the main factor for Alvesco is convenience. However, if only the low dosages are approved, the lack of flexibility will give Alvesco difficulties in the market.
Altana and Sanofi are also developing a DPI Alvesco/formoterol combination, currently in phase IIb for asthma. However, formoterol is dosed twice-a-day, so this would not offer convenience over Advair.
Ariflo – GlaxoSmithKline (GSK)
Ariflo is an oral phosphodiesterase 4 inhibitor (PDE 4). Inhibition of PDE 4 has been shown to relax smooth muscles in airways, reduce the activation of inflammatory cells, and affect the activity of pulmonary nerves. Ariflo differs from the methylxanthines, which are non-specific PDE inhibitors, inhibiting PDE 3 more than PDE 4. The cardiovascular side effects of the methylxanthines are most likely mediated by PDE 3 inhibition.
In September 2003, Ariflo was reviewed by an FDA Advisory Committee, who recommended that Ariflo needed long-term efficacy studies to confirm its maintenance of effect in COPD. Out of 4 pivotal studies, in patients with moderate to severe COPD, only two had shown statistical significance in the primary endpoint of a mean change in FEV1. In both the mean increase was 10 ml, while placebo declined 30ml and 20 ml. Only 1 study reached statistical significance on another primary endpoint, a quality-of-life instrument (St. George's Respiratory Questionnaire; SGRQ). Ariflo was generally found to be safe. The main side effects of concern were gastrointestinal. While the trials did not find signs of inflammation of the arteries of the bowel, a finding seen in pre-clinical studies that can lead to lack of blood flow to the intestines, the follow-up for potential problem cases was inconsistent. In October 2003, GlaxoSmithKline received an approvable letter, and the recommended additional trial is ongoing. GlaxoSmithKline is not releasing details on the timing. Given the poor efficacy, we are doubtful this drug will be approved. Another PDE 4 inhibitor in development, Daxas (see below) is more potent.
Daxas is an oral PDE 4 inhibitor, like Ariflo but more potent. While a 24-week study of patients with moderate to severe COPD showed a 74 -97 ml improvement in FEV1 compared to placebo, a 1-year trial of patients with severe to very severe COPD resulted in a lower, 39 - 48 ml improvement compared to placebo. The first study showed a reduction in mild exacerbations, but not more severe ones (though the rates of severe exacerbations were low). The study in more severe patients did not show a significant reduction in overall exacerbations, but found an 18% reduction in exacerbations requiring oral steroids. Altana has raised the possibility that the lower than expected reduction in the more severe patients was due to the fact that the rate of exacerbations in the overall population was lower than anticipated. In any case, Pfizer dropped out of the project at the time the results for more severe COPD were announced.
It is unclear whether the FEV1 improvement seen with Daxas is due to a bronchodilator effect or anti-inflammatory effect. While the change in lung function appeared greater than that seen in the Ariflo studies (which were done in moderate to severe patients), they are still modest, though comparable to changes seen with inhaled corticosteroids. However, the reduction in exacerbations appears to be lower or at the low end of what has been seen with corticosteroids, and significantly less than combination LABA/ICS products.
On November 15, Altana announced that they had withdrawn their EMEA submission as further data was needed. This should come from a 1-year phase III trial that has completed enrollment. Results should be announced in 2006 (Altana will not be more specific with a date). If positive, this study will help form the basis for a US submission and European resubmission. The company has also planned additional studies beginning in 2006 in case results are weak. No studies lasting over a year have been done.
Overall, given the data to date, we think Daxas has a greater chance of approval than Ariflo, and while the results are not as strong as we would like to see, we think it is likely to be approved. However, due to its modest effects, we think its market penetration will be limited.
DRUGS IN EARLY DEVELOPMENT
Flutiform is a combination of the inhaled corticosteroid fluticasone with the long-acting bronchodilator formoterol, being developed as an HFA metered-dose inhaler for asthma using a fixed dosing schedule. It has finished its phase II trial and a phase III trial is to begin in January of 2006. SkyePharma plans to submit their NDA by mid 2007, and is hoping for approval in the first half of 2009. While not currently under development for COPD, the drugs in the combination are already used for COPD, and we anticipate off-label use. Since these are well-established drugs, it is likely the combination will work and be as effective as others on the market. While this is a strong combination of what are probably the best agents currently in their classes, it is unclear whether Flutiform offers a significant clinical benefit. As a latecomer, Flutiform will likely gain a minority share, but will likely need to compete after a few years with new once-a-day preparations now in phase II development.
GSK159797 – GlaxoSmithKline (GSK) and Theravance (THRX)
GSK159797 is an inhaled, once-daily beta-agonist in phase II development for asthma and COPD. It is to be delivered via DPI. GSK159797 is one of a number of compounds in GlaxoSmithKline’s and Theravance’s “Beyond Advair” collaboration, whose goal is to produce a next generation Advair, consisting of a once-a-day LABA and ICS. GSK159797 was contributed by Theravance. Clinical results are only available for an asthma trial of 20 patients, where GSK15979 showed increases in FEV1 at 24 hours of 460 ml to 540 ml, compared to an increase of 130 ml for placebo. These are in the range of what has been seen at 12 hours with existing LABA treatment in asthma, though on the low end. Importantly, the heart rate was only minimally increased by the drug (a potential side effect of beta-agonists). It is too soon to tell whether the drug will be successful in achieving 24 hour control for COPD. If it does succeed, we do not think that a 24-hour LABA alone will generate much market interest, but if combined with a 24-hour corticosteroid as planned, it would be quite popular (GSK has at least one in phase II study). Of some concern was a recent announcement that phase IIb study initiation will not occur by the end of the 2005 due to potential formulation issues. An update on projected timing for the study is expected to be provided, though details on when the update will come have not been released.
QAB149 – Novartis (NVS) and SkyePharma (SKYE)
Like GSK159797, QAB149 is an inhaled once-daily beta-agonist. It is a Novartis drug being developed with SkyePharma’s powder formulation and has completed several phase II trials. It has a rapid onset of action, like that of Foradil and albuterol. Again, results are available only from an asthma trial, though the company has said that QAB149 showed good efficacy in a phase IIb trial for COPD. In 42 patients with intermittent or persistent asthma, the increase in FEV1 at 24 hours was 10.6% higher than for placebo. While on the order of some data on twice-a-day LABAs, the effect appears on the low end. Like GSK159797, there is not enough information to tell if the drug will be successful in COPD. If it is, while it would likely take share from other LABAs, we do not think it will have major use as a stand-alone agent.
NVA237 – Novartis (NVS), Vectura (VEC.L), and Sosei
Like Spiriva, NVA237 is a long-acting muscarinic antagonist with once-a-day dosing that recently entered phase IIb testing for COPD. Though the compound is off-patent, it was never before licensed for COPD. NVA237 was originated by Vectura and Sosei and has been licensed to Novartis. It reportedly has a fast onset of action. In a IIa trial of patients with COPD, NVA237 showed good efficacy, on the order of Spiriva. There was a high incidence of headaches (28.9%), but the study did note there was no dose-dependent increase in adverse effects, including placebo. If this is not a side effect of the drug, then it will be a strong competitor to Spiriva, though as first to market we think Spiriva will retain a majority share.
NVA237 and QAB149 are also being developed as a combination, NVA237/QAB149 (Novartis, Vectura, and Sosei). Even if QAB149 turns out to be slightly weaker than twice-a-day LABAs, we think this combination would take significant share in the anticholinergic segment, and would be particularly useful in less severe disease. We do not think the combination alone would displace a LABA/ICS combination like Advair, as patients on the LABA/ICS combination are those who benefit from a steroid. While NVA237/QAB149 plus and ICS would compete against a LABA/ICS plus Spiriva or QAB149, we think that the LABA/ICS combination is well-established and there is unlikely to be across-the-board switching. Even though there is some logic in using the NVA237/QAB149 combination as it combines the bronchodilators into one, there may be some concerns, particularly in light of the above-mentioned SMART results in asthma patients, about patients not being compliant with their inhaled steroids and just relying on the bronchodilator combination. Hence we think it will take a minority share in patients who need all three. REVENUE MODELS
We have added 9 new revenue models for COPD: Advair, Symbicort, Flutiform, GSK159797-ICS, Spiriva, NVA237, NVA237-QAB149, Daxas, and Xopenex.
LABA/ICS Combinations
Advair – GlaxoSmithKline (GSK)
We project Advair’s growth will slow and it will lose share to new entrants on the market, especially to generics once its patents expire and to GSK’s new once-a-day formulation. Our revenue model assumes entrance of a generic in the US in 2010. The 5 and 10-year US revenue projections for the COPD market are $585.7 million and $168.0 million, with corresponding worldwide revenues of $1.7 billion and $568.8 million.
We project Symbicort will start to gain significant share, but this will be limited by other entrants with enhanced features. It will also be somewhat effected by a generic for Advair. Projections for 5 and 10-year US revenues are $298.8 and $121.3, with worldwide revenues of $787.7 million and $301.9 million.
We believe Flutiform will benefit from its combination of drugs with very desirable characteristics. However, it will be limited by its late entrance, as well as the entrance of a new once-a-day preparation from the Beyond Advair drugs. We project 5 and 10-year US revenues of $217.8 million and $84.7 million, with worldwide revenues of $385.2 million and $220.6 million.
GSK159797 – ICS GlaxoSmithKline (GSK) and Theravance (THRX)
While we are concerned about the recently announced formulation issue delaying phase IIb testing, we think that a once-a-day combination will arise out of the Beyond Advair program. We are projecting 10-year US revenue for the GSK159797 – ICS combination of $1.1 billion, with $2.3 billion worldwide.
Anticholinergics and Combinations
Spiriva – Pfizer (PFE) and Boehringer Ingelheim
We believe Spiriva sales will continue to grow until NVA237, and the combination anticholinergic-beta-agonist NVA237-QAB149, enter the market. We project 5 and 10-year US revenues of $1.0 billion and $553.8 million, with worldwide revenues of $2.2 billion and $1.2 billion.
NVA237 – Novartis (NVS), Vectura (VEC.L), and Sosei
We believe NVA237 will take a significant share of the anticholinergic segment, but will remain behind Spiriva. Projected 5 and 10-year US revenues are $87.7 million and $307.2 million, with worldwide revenues of $173.0 million and $669.9 million.
NVA237/QAB149 – Novartis (NVS), Vectura (VEC.L), and Sosei
This combination of a long-acting anticholinergic and beta-agonist should be popular, and pass the single agent drugs in share. We project 10-year US revenue of $593.9 million, with worldwide revenue of $1.3 billion.
Phosphodiesterase Inhibitor
Daxas has demonstrated mixed results and does not appear to be a breakthrough therapy. However, it may be of added benefit to selected patients. We project 5 and 10-year revenues of $61.9 million and $161.7 million, with worldwide revenues of $124.6 million and $351.6 million.
Short-acting Beta Agonist
Xopenex HFA– Sepracor (SEPR) and 3M (MMM)
The clinical benefit for Xopenex HFA has not been clearly shown, though the theoretical benefit and that seen with the nebulized form is likely to carry some weight. However, we do not think Xopenex will gain significant share until the CFC ban at the end of 2008. Subsequently, we think it will succumb to competition from generic HFA drugs once they enter the market. We project 5 and 10-year US revenues of $245.7 million and $222.5 million. Xopenex is not currently being developed outside of the US.
Compared to short-acting beta-agonists, short-acting anticholinergics are more potent at regular doses in COPD. Anticholinergics are more effective in COPD than in asthma, and hence are commonly used in COPD. The short-acting anticholinergics have a slower onset of action (20-30 minutes vs 1-3 minutes) and longer duration than the beta-agonists, making them less suitable for as needed use. Nevertheless, they are recommended in guidelines, and a number of physicians do prescribe them for as needed use, particularly since some patients may respond better to anticholinergics than beta-agonists. For example, in one study, 35% of COPD patients showed an improvement in FEV1 with either beta-agonists or anticholinergics, 27% responded to albuterol alone, and 11% responded to the anticholinergic Atrovent (Boehringer Ingelheim) alone. (Atrovent is the sole single-agent anticholinergic for use in a portable inhaler in the US.) As noted above, since a long-acting anticholinergic was only recently introduced in the US, short-acting anticholinergics have also been used for maintenance treatment.
Anticholinergics can be used alone or in combination with beta-agonists, corticosteroids (for patients with frequent exacerbations), or both. Currently, the most commonly used anticholinergic is a combination medication called Combivent (Boehringer Ingelheim), which includes albuterol and the active ingredient of Atrovent. The combination has been shown to work better than either component alone (an improvement in FEV1 for single agents of about 25% versus 32% for the combination) and of course is more convenient. As a result, Combivent is prescribed about 4 times more than Atrovent. Its major disadvantage is its short duration of action: the usual dosage is 2 puffs 4 times a day. Though it has a comparative price advantage, this makes it vulnerable to longer-acting medications, such as Spiriva (see below), launched in 2004.
Long-acting Inhaled Bronchodilators
The long-acting inhaled bronchodilators are recommended for maintenance treatment of patients with persistent symptoms, usually moderate or severe disease. If an agent is insufficient, it can be switched or combined with one that has a different mechanism of action.
Serevent (GlaxoSmithKline) is the oldest long-acting inhaled bronchodilator in the US, approved for asthma in 1994 and for COPD in 1998. It is given twice daily. The active part of the molecule is the same as for albuterol. Studies have not shown dramatic benefits with Serevent use over other treatment, though there is some evidence for a reduction in COPD exacerbations compared to Atrovent (20.7% vs 30.8% of patients having their first exacerbation in 12 weeks). In asthma, Serevent had negative publicity arising out of the SMART trial (Salmeterol Multi-center Asthma Research Trial), where adding Serevent to usual treatment resulted in a small but significant increase in mortality. (There was no increase, however, in patients also receiving corticosteroids.) That led to a black-box warning in 2003. More recently, on November 18, 2005, the FDA requested changes in the label for Serevent, as well as Foradil and Advair (see below), recommending that these agents only be used for asthma patients failing corticosteroids. Thus far, the concern has not extended to COPD patients, and guidelines have not changed recommendations that in COPD these agents be used before corticosteroids. In COPD the long-acting beta-agonists have not been seen to worsen exacerbations, as they have in asthma. Nevertheless, the warning may raise concern over patients with an asthmatic component to their disease. The patent on the active ingredient of Serevent is due to expire in 2008 in the USA and 2005 in most of Europe.
Competitor Foradil (Schering-Plough, Novartis, Astellas), approved in 2001 in the US, has a faster onset of action than Serevent, but in direct comparisons of stable doses, this has not been shown to translate into a definite clinical advantage, with the exception of earlier improvements in FEV1. Like Serevent, Foradil is given twice daily and has also shown some evidence of a clinical benefit above Atrovent. Foradil has been hampered because the device is less convenient to use: unlike Serevent, blisters containing the medication must be put into the device one at a time. The US patent for Foradil’s active ingredient is set to expire in February 2006, and has expired in other major countries. Another competitor with the same active ingredient, Oxis (AstraZeneca), is available in Europe, where a generic version has also appeared.
Despite the fact that they are recommended as initial maintenance therapy for COPD, market share for these LABAs is relatively low, due to competition from Advair (see below), a combination product.
Spiriva (Pfizer, Boehringer Ingelheim) is the sole long-acting anti-cholinergic agent, approved in the US in January 2004. It is approved only for COPD, not for asthma. Unlike the other currently approved long-acting bronchodilators, it is given once-a-day. Spiriva has shown improvements in lung function greater than Serevent, and in a comparative trial had a numerically greater reduction in exacerbations (the difference between Spiriva and placebo was statistically significant, whereas that between Serevent and placebo was not). The only adverse event significantly worse with Spiriva was dry mouth (8.2% vs 1.7% Serevent). Spiriva has shown better symptom control than Atrovent, and there is preliminary evidence it may slow the decline in FEV1. A large trial (UPLIFT) to better evaluate Spiriva’s ability to slow progression of COPD completed enrollment in March 2004, with results expected in 2008. As noted above, to date no treatment (other than smoking cessation) has been shown to reduce progression.
At this year’s European Respiratory Society meeting, data from a 6-week trial was presented showing greater changes in various measures of FEV1 for Spiriva plus Foradil versus a free combination of Serevent plus the corticosteroid Flovent. This study was aimed at competitor Advair. However, the results are not entirely unexpected, since the Spiriva-Foradil combination involved two bronchodilators. We will speak more about this and Spiriva’s competitive position in the market summary below.
Inhaled Corticosteroids (ICS)
Glucocorticoids act at a number of levels to reduce inflammation. These include reducing the number and availability of inflammatory cells and inhibiting the production and release of chemicals that mediate the inflammatory response. Due to their numerous side effects in the body, oral corticosteroids are only used for short periods to treat exacerbations of COPD. ICSs, on the other hand, are generally thought to be safe for long-term use, though one large study has shown a decline in bone density and an increased risk of bruising.
As noted above, in COPD, ICSs are recommended only after failure of bronchodilators, though in practice they are commonly used earlier on. Also, single agent ICSs have not actually been approved for COPD, but are used nonetheless.
Pharmacological properties of different ICSs influence how effective they are in the respiratory system and the degree of systemic side effects. For example, particle size and formulation influences how much gets to the lung after an inhaled dose and how much is deposited in the mouth, where it can be swallowed and potentially have a systemic effect. Even if a drug is swallowed, if it is metabolized to a high degree in the liver (resulting in what is called low bioavailability), it will also have less systemic absorption. Products that dissolve better in lipid solutions (lipophilicity) than in water are thought to have a more prolonged action in the lung.
Due to their advantage in factors such as these, Flovent (GlaxoSmithKline) and Pulmicort (AstraZeneca) are the most commonly used single agents (Pulmicort is commonly used as a nebulized formulation). In addition, the active ingredient of Flovent is used in Advair, and the active ingredient of Pulmicort is being developed as a combination product with the long-acting beta-agonist formoterol (see Symbicort below).
An ICS may be used in a fixed combination for convenience (Advair is the only combination currently available in the US), or alone, when they are to be used with a bronchodilator other than the one in Advair or when more flexible dosing is required.
LABA/ICS Combination
Advair (GlaxoSmithKline) is a combination of salmeterol (the active ingredient of the LABA Serevent) and fluticasone (the active ingredient of the ICS Flovent). Advair has shown significant effects on pulmonary function and symptoms beyond those compared to either component alone, without significantly increasing side effects. While Advair has demonstrated numerically lower rates of exacerbations than its components, the results have not been statistically significant. As expected from its ICS component, the largest benefit for Advair in reducing exacerbations is in severe disease, but it is commonly used earlier on, as well.
An uncontrolled study has suggested that use of both individual components in Advair treatment reduces mortality compared to patients who do not use a steroid or long-acting beta-agonist. A large three-year study (TORCH) evaluating this for Advair, its components, and placebo is currently underway and results are expected in 2006. In addition, when Advair was approved for COPD, GSK had committed to further studies on Advair’s effects on COPD exacerbations and bone mineral density. The final reports for these are due in August and December 2007.
The clinical benefits and convenience of Advair has propelled it to the best selling (in terms of revenue) inhaled pulmonary drug, with US and worldwide sales of $2.4 billion and $4.5 billion respectively in 2004. An estimated 30% of the sales are due to COPD. GSK’s patent on the specific combination of active ingredients in Advair expires in 2010 in the US and 2013 in Europe. While there may be more difficulties in developing generic inhaled combination products compared to oral ones, we believe the market is so large that a generic substitute for Advair will arise.
Current Market Summary
For as needed medications, albuterol is the market leader, though sales figures are not high due to generics. Revenues are likely to increase significantly after 2008 when the CFC bearing generics are banned. Unless 3M grants more licenses for generic albuterol HFA, this is likely to last until between 2010 to 2017, depending on which patents for the HFA formulations are deemed valid. Without more data showing a benefit, Xopenex HFA is unlikely to gain significant share until the CFC ban, after which we believe it will have modest penetration, but lose share again when generic HFA formulation enter. Since the anticholinergics are priced above the HFA albuterol formulations, the switch to HFA is unlikely to affect anticholinergic as needed usage.
For maintenance bronchodilators, Advair is by far the best selling. It offers a combination of a bronchodilator and a steroid to fight inflammation and as a result is much more popular than the single long-acting beta-agonists, Serevent and Foradil. Single agent corticosteroids are used about 50-60% as much as Advair. The anticholinergics are also commonly used, with Combivent currently the most prescribed. Atrovent and Combivent are likely used alone as maintenance medications in less severe patients, or together with Advair (or Combivent plus an ICS) in more severe patients. Spiriva has shown strong growth since its introduction, and we believe that due to its convenience and efficacy, it will increasingly erode Atrovent and Combivent share. For example, we think Spiriva plus Advair will generally be preferred over Combivent plus a steroid for patients with more severe disease. Spiriva is also likely to expand the anticholinergic segment somewhat, for example in combination with Advair in patients who did not want to use the short-acting anticholinergics, in place of LABAs, or inducing more patients on as needed albuterol to use Spiriva as a maintenance medication.
Spiriva’s superiority over Serevent, along with the study showing greater improvement in lung function for Spiriva plus Foradil compared to the components of Advair, raises questions about whether Spiriva alone or with a beta-agonist should be used instead of Advair, particularly in patients with less severe disease. This is certainly more in line with guidelines, which recommend steroid use only in severe COPD. But while we think Spiriva will take some share from Advair in new patients with less severe disease, we believe that for many patients, physicians will view the corticosteroid component as important, and the impact on Advair will be relatively small.
Existing treatment leaves a great need for drugs that alter the basic inflammatory process of COPD. However, with only a couple exceptions, most drugs in late stage development are attempts at improving existing treatment. Particularly since compliance is a big problem in COPD, one trend is the development of inhaled drugs dosed once-a-day.
DRUGS IN DEVELOPMENT
DRUGS IN NDA
Foradil Certihaler - Schering-Plough (SGP), Novartis (NVS), SkyePharma (SKYE)
Foradil Certihaler is a multidose dry powder formulation of Foradil Aerolizer, which is a single dose DPI. Hence the advantage of the new formulation is convenience of the multi-dose feature. While it is likely to do better than and take share from Foradil (and Serevent), we believe the single agent LABAs have limited market potential.
Arformoterol – Sepracor (SEPR) and Novartis (NVS)
Arformoterol is a single enantiomer form of the active ingredient of Foradil, being developed as the first nebulized long-acting beta-agonist. As mentioned above, enantiomers are mirror image molecules. Normally, formulations include both molecules. The NDA was submitted on December 13, 2005. Sepracor has completed two phase III studies and a chronic safety study. There is little comparative clinical information on the drug, but we think it is likely to be approved for the more limited nebulizer market.
DRUGS IN PHASE III DEVELOPMENT
Asmanex - Schering-Plough (SGP)
Asmanex is a long-acting DPI corticosteroid, which unlike current formulations is usually dosed once-a-day. It is already approved for use in asthma (in March 2005), and was launched late in the third quarter. Of approved ICSs, Asmanex has the highest affinity for the corticosteroid receptor. It has a number of pharmacologic properties thought to reduce systemic effects, though it shares these with other competitors. Its major point of differentiation is convenience.
Despite its convenience, we think without showing a more pronounced clinical benefit, uptake will be slow in competition against established drugs. It is unlikely to affect the share of market leader Advair, unless it is formulated into a combination with a once-a-day bronchodilator. A combination of Asmanex and the LABA Foradil (Novartis, Schering-Plough, Astellas) is in phase I development for COPD and phase II for asthma. We have doubts about whether this medicine will provide any benefit above current treatment, however, as Foradil requires twice-a-day dosing.
Symbicort is a combination of the long-acting bronchodilator formoterol (the active ingredient in Foradil and Oxis - the latter is AZN’s drug) and budesonide (the active ingredient in Pulmicort). It is a twice daily formulation, being developed for an MDI in the US (according to AstraZeneca, the Turbohaler DPI formulation is not being developed in the US due to the regulatory burden regarding manufacturing issues). Currently, an NDA was submitted in September 2005 for asthma, and it is in phase III development for COPD. It is already approved in Europe, and we think approval in the US is likely, though there have been manufacturing issues. (Patents are due to expire 2012 in most major European countries, and approximately in 2014 in the US.) Symbicort has been shown to reduce exacerbations beyond formoterol alone and improve lung function beyond budesonide alone. It is a direct competitor for Advair. There have not been adequate trials comparing Symbicort with Advair in COPD, though the faster onset of Symbicort’s LABA is likely to be an advantage. On the other hand, if swallowed the corticosteroid in Symbicort has a greater likelihood of reaching the circulation and causing systemic effects.
In asthma, AstraZeneca has been supporting flexible dosing of Symbicort, where patients use baseline Symbicort and increase usage as needed (instead of adding short-acting agents). Symbicort is more suitable for this than Advair, because of the faster onset of action of the beta-agonist in Symbicort. While this may help Symbicort gain an advantage in asthma, the concept of flexible dosing has less relevance to COPD, where there is less of a reversible component. On the other hand, patients with COPD have a low compliance in medication usage (< 50% in one study), suggesting they may use their medications to some extent on a more as-needed basis anyways. As a result, some patients may prefer Symbicort. In addition, physicians typically prescribing Symbicort for their asthma patients are also likely to use it for their COPD patients. AstraZeneca has not disclosed whether the US submission for the MDI formulation is for fixed or flexible dosing.
We believe Symbicort will be used off-label for COPD after approved for asthma, and is likely to be approved for COPD, as well. While we think that it will gain a healthy share, due to its late entrance and lack of a dramatic clinical superiority, we do not think it will engender across-the-board switching in patients using Advair for COPD.
Alvesco – Altana (AAA) and Sanofi-Aventis (SNY)
Alvesco is a once-a-day corticosteroid (twice-a-day for high doses) in phase III development for asthma. It is delivered by an HFA MDI. We include it in our analysis, as many of the existing steroids used in COPD have only been approved for asthma. Alvesco is a prodrug that is activated in the lungs. It scores high on the list of pharmacologic properties of a desired ICS. In addition to convenience, a significant advantage is a lower incidence of oral fungal infections, a side effect of corticosteroid deposition in the mouth. However, of concern was a study of high doses showing an increased rate of cataracts with high dose Alvesco (2.4% for Alvesco 160 microgram twice-a-day; 6.2% for Alvesco 320 micrograms twice-a-day, 0.7% for Flovent 440 micrograms twice-a-day, and 0.7% for placebo).
Alvesco received an FDA approvable letter in 2004, but further clinical information was needed. One trial evaluating the eye effects of Alvesco has already been completed. While the company has stated it showed good safety, the data have not yet been released. Two additional trials, 12 week and 16 week studies looking at once-a-day versus twice-a-day dosing, were instituted this year and are slated to be finished August 2006. Alvesco was approved in the first European country in April 2004, but only for the lower dosages of the drug.
Despite company reassurances, we are concerned that the high dosages do lead to a higher rate of cataracts and will not be approved in the US either. That means the main factor for Alvesco is convenience. However, if only the low dosages are approved, the lack of flexibility will give Alvesco difficulties in the market.
Altana and Sanofi are also developing a DPI Alvesco/formoterol combination, currently in phase IIb for asthma. However, formoterol is dosed twice-a-day, so this would not offer convenience over Advair.
Ariflo – GlaxoSmithKline (GSK)
Ariflo is an oral phosphodiesterase 4 inhibitor (PDE 4). Inhibition of PDE 4 has been shown to relax smooth muscles in airways, reduce the activation of inflammatory cells, and affect the activity of pulmonary nerves. Ariflo differs from the methylxanthines, which are non-specific PDE inhibitors, inhibiting PDE 3 more than PDE 4. The cardiovascular side effects of the methylxanthines are most likely mediated by PDE 3 inhibition.
In September 2003, Ariflo was reviewed by an FDA Advisory Committee, who recommended that Ariflo needed long-term efficacy studies to confirm its maintenance of effect in COPD. Out of 4 pivotal studies, in patients with moderate to severe COPD, only two had shown statistical significance in the primary endpoint of a mean change in FEV1. In both the mean increase was 10 ml, while placebo declined 30ml and 20 ml. Only 1 study reached statistical significance on another primary endpoint, a quality-of-life instrument (St. George's Respiratory Questionnaire; SGRQ). Ariflo was generally found to be safe. The main side effects of concern were gastrointestinal. While the trials did not find signs of inflammation of the arteries of the bowel, a finding seen in pre-clinical studies that can lead to lack of blood flow to the intestines, the follow-up for potential problem cases was inconsistent. In October 2003, GlaxoSmithKline received an approvable letter, and the recommended additional trial is ongoing. GlaxoSmithKline is not releasing details on the timing. Given the poor efficacy, we are doubtful this drug will be approved. Another PDE 4 inhibitor in development, Daxas (see below) is more potent.
Daxas is an oral PDE 4 inhibitor, like Ariflo but more potent. While a 24-week study of patients with moderate to severe COPD showed a 74 -97 ml improvement in FEV1 compared to placebo, a 1-year trial of patients with severe to very severe COPD resulted in a lower, 39 - 48 ml improvement compared to placebo. The first study showed a reduction in mild exacerbations, but not more severe ones (though the rates of severe exacerbations were low). The study in more severe patients did not show a significant reduction in overall exacerbations, but found an 18% reduction in exacerbations requiring oral steroids. Altana has raised the possibility that the lower than expected reduction in the more severe patients was due to the fact that the rate of exacerbations in the overall population was lower than anticipated. In any case, Pfizer dropped out of the project at the time the results for more severe COPD were announced.
It is unclear whether the FEV1 improvement seen with Daxas is due to a bronchodilator effect or anti-inflammatory effect. While the change in lung function appeared greater than that seen in the Ariflo studies (which were done in moderate to severe patients), they are still modest, though comparable to changes seen with inhaled corticosteroids. However, the reduction in exacerbations appears to be lower or at the low end of what has been seen with corticosteroids, and significantly less than combination LABA/ICS products.
On November 15, Altana announced that they had withdrawn their EMEA submission as further data was needed. This should come from a 1-year phase III trial that has completed enrollment. Results should be announced in 2006 (Altana will not be more specific with a date). If positive, this study will help form the basis for a US submission and European resubmission. The company has also planned additional studies beginning in 2006 in case results are weak. No studies lasting over a year have been done.
Overall, given the data to date, we think Daxas has a greater chance of approval than Ariflo, and while the results are not as strong as we would like to see, we think it is likely to be approved. However, due to its modest effects, we think its market penetration will be limited.
DRUGS IN EARLY DEVELOPMENT
Flutiform is a combination of the inhaled corticosteroid fluticasone with the long-acting bronchodilator formoterol, being developed as an HFA metered-dose inhaler for asthma using a fixed dosing schedule. It has finished its phase II trial and a phase III trial is to begin in January of 2006. SkyePharma plans to submit their NDA by mid 2007, and is hoping for approval in the first half of 2009. While not currently under development for COPD, the drugs in the combination are already used for COPD, and we anticipate off-label use. Since these are well-established drugs, it is likely the combination will work and be as effective as others on the market. While this is a strong combination of what are probably the best agents currently in their classes, it is unclear whether Flutiform offers a significant clinical benefit. As a latecomer, Flutiform will likely gain a minority share, but will likely need to compete after a few years with new once-a-day preparations now in phase II development.
GSK159797 – GlaxoSmithKline (GSK) and Theravance (THRX)
GSK159797 is an inhaled, once-daily beta-agonist in phase II development for asthma and COPD. It is to be delivered via DPI. GSK159797 is one of a number of compounds in GlaxoSmithKline’s and Theravance’s “Beyond Advair” collaboration, whose goal is to produce a next generation Advair, consisting of a once-a-day LABA and ICS. GSK159797 was contributed by Theravance. Clinical results are only available for an asthma trial of 20 patients, where GSK15979 showed increases in FEV1 at 24 hours of 460 ml to 540 ml, compared to an increase of 130 ml for placebo. These are in the range of what has been seen at 12 hours with existing LABA treatment in asthma, though on the low end. Importantly, the heart rate was only minimally increased by the drug (a potential side effect of beta-agonists). It is too soon to tell whether the drug will be successful in achieving 24 hour control for COPD. If it does succeed, we do not think that a 24-hour LABA alone will generate much market interest, but if combined with a 24-hour corticosteroid as planned, it would be quite popular (GSK has at least one in phase II study). Of some concern was a recent announcement that phase IIb study initiation will not occur by the end of the 2005 due to potential formulation issues. An update on projected timing for the study is expected to be provided, though details on when the update will come have not been released.
QAB149 – Novartis (NVS) and SkyePharma (SKYE)
Like GSK159797, QAB149 is an inhaled once-daily beta-agonist. It is a Novartis drug being developed with SkyePharma’s powder formulation and has completed several phase II trials. It has a rapid onset of action, like that of Foradil and albuterol. Again, results are available only from an asthma trial, though the company has said that QAB149 showed good efficacy in a phase IIb trial for COPD. In 42 patients with intermittent or persistent asthma, the increase in FEV1 at 24 hours was 10.6% higher than for placebo. While on the order of some data on twice-a-day LABAs, the effect appears on the low end. Like GSK159797, there is not enough information to tell if the drug will be successful in COPD. If it is, while it would likely take share from other LABAs, we do not think it will have major use as a stand-alone agent.
NVA237 – Novartis (NVS), Vectura (VEC.L), and Sosei
Like Spiriva, NVA237 is a long-acting muscarinic antagonist with once-a-day dosing that recently entered phase IIb testing for COPD. Though the compound is off-patent, it was never before licensed for COPD. NVA237 was originated by Vectura and Sosei and has been licensed to Novartis. It reportedly has a fast onset of action. In a IIa trial of patients with COPD, NVA237 showed good efficacy, on the order of Spiriva. There was a high incidence of headaches (28.9%), but the study did note there was no dose-dependent increase in adverse effects, including placebo. If this is not a side effect of the drug, then it will be a strong competitor to Spiriva, though as first to market we think Spiriva will retain a majority share.
NVA237 and QAB149 are also being developed as a combination, NVA237/QAB149 (Novartis, Vectura, and Sosei). Even if QAB149 turns out to be slightly weaker than twice-a-day LABAs, we think this combination would take significant share in the anticholinergic segment, and would be particularly useful in less severe disease. We do not think the combination alone would displace a LABA/ICS combination like Advair, as patients on the LABA/ICS combination are those who benefit from a steroid. While NVA237/QAB149 plus and ICS would compete against a LABA/ICS plus Spiriva or QAB149, we think that the LABA/ICS combination is well-established and there is unlikely to be across-the-board switching. Even though there is some logic in using the NVA237/QAB149 combination as it combines the bronchodilators into one, there may be some concerns, particularly in light of the above-mentioned SMART results in asthma patients, about patients not being compliant with their inhaled steroids and just relying on the bronchodilator combination. Hence we think it will take a minority share in patients who need all three.
REVENUE MODELS
We have added 9 new revenue models for COPD: Advair, Symbicort, Flutiform, GSK159797-ICS, Spiriva, NVA237, NVA237-QAB149, Daxas, and Xopenex.
LABA/ICS Combinations
Advair – GlaxoSmithKline (GSK)
We project Advair’s growth will slow and it will lose share to new entrants on the market, especially to generics once its patents expire and to GSK’s new once-a-day formulation. Our revenue model assumes entrance of a generic in the US in 2010. The 5 and 10-year US revenue projections for the COPD market are $585.7 million and $168.0 million, with corresponding worldwide revenues of $1.7 billion and $568.8 million.
We project Symbicort will start to gain significant share, but this will be limited by other entrants with enhanced features. It will also be somewhat effected by a generic for Advair. Projections for 5 and 10-year US revenues are $298.8 and $121.3, with worldwide revenues of $787.7 million and $301.9 million.
We believe Flutiform will benefit from its combination of drugs with very desirable characteristics. However, it will be limited by its late entrance, as well as the entrance of a new once-a-day preparation from the Beyond Advair drugs. We project 5 and 10-year US revenues of $217.8 million and $84.7 million, with worldwide revenues of $385.2 million and $220.6 million.
GSK159797 – ICS GlaxoSmithKline (GSK) and Theravance (THRX)
While we are concerned about the recently announced formulation issue delaying phase IIb testing, we think that a once-a-day combination will arise out of the Beyond Advair program. We are projecting 10-year US revenue for the GSK159797 – ICS combination of $1.1 billion, with $2.3 billion worldwide.
Anticholinergics and Combinations
Spiriva – Pfizer (PFE) and Boehringer Ingelheim
We believe Spiriva sales will continue to grow until NVA237, and the combination anticholinergic-beta-agonist NVA237-QAB149, enter the market. We project 5 and 10-year US revenues of $1.0 billion and $553.8 million, with worldwide revenues of $2.2 billion and $1.2 billion.
NVA237 – Novartis (NVS), Vectura (VEC.L), and Sosei
We believe NVA237 will take a significant share of the anticholinergic segment, but will remain behind Spiriva. Projected 5 and 10-year US revenues are $87.7 million and $307.2 million, with worldwide revenues of $173.0 million and $669.9 million.
NVA237/QAB149 – Novartis (NVS), Vectura (VEC.L), and Sosei
This combination of a long-acting anticholinergic and beta-agonist should be popular, and pass the single agent drugs in share. We project 10-year US revenue of $593.9 million, with worldwide revenue of $1.3 billion.
Phosphodiesterase Inhibitor
Daxas has demonstrated mixed results and does not appear to be a breakthrough therapy. However, it may be of added benefit to selected patients. We project 5 and 10-year revenues of $61.9 million and $161.7 million, with worldwide revenues of $124.6 million and $351.6 million.
Short-acting Beta Agonist
Xopenex HFA– Sepracor (SEPR) and 3M (MMM)
The clinical benefit for Xopenex HFA has not been clearly shown, though the theoretical benefit and that seen with the nebulized form is likely to carry some weight. However, we do not think Xopenex will gain significant share until the CFC ban at the end of 2008. Subsequently, we think it will succumb to competition from generic HFA drugs once they enter the market. We project 5 and 10-year US revenues of $245.7 million and $222.5 million. Xopenex is not currently being developed outside of the US.