Respiratory Disorders Set to Benefit from Influx of Novel Targeted Biologic Therapies
Written By Yasser Mushtaq, Senior Analyst for GBI Research
The respiratory therapy area consists of indications that affect the respiratory system in different ways, such as the scarring of lung tissue and excessive production of mucus in the airways, ultimately decreasing lung function. The most prominent respiratory disorders are asthma and chronic obstructive disease (COPD).
Both these indications are characterized by a high prevalence across much of the developed world, although trends in prevalence and causes of diseases vary considerably, with COPD being strongly associated with older populations, while asthma is the most common chronic disease among children and young adults – although it is also highly prevalent in the elderly.
Asthma symptoms can vary from mild to severe, and include breathlessness, a tight chest, wheezing and coughing, which may be particularly severe at night and in the morning. It is possible for symptoms to get significantly worse over a short period, commonly referred to as an asthma attack. COPD symptoms are different to those of asthma, even though many of the same therapies are used to treat both indications. Chronic cough and sputum production may appear a number of years prior to airflow obstruction (GOLD, 2015).
There are three common pathophysiological components in COPD and asthma: airway inflammation, airway obstruction and airway hyper-responsiveness. Chronic inflammation is a key component of both diseases, although in each disease there are distinct characteristics. For example, in asthma it is known that eosinophils, mast cells and CD4 T lymphocytes are the dominant types of inflammatory cells, while in COPD, there are a greater number of neutrophils, macrophages and CD8 T lymphocytes (Athanazio, 2012).
There are, however, elements of overlap between the two diseases. For instance, asthmatics who smoke or who have severe disease with airway obstruction have increased numbers of neutrophils in the airways, as in COPD. Furthermore, in both diseases, smoking is known to cause neutrophilic inflammation. Additionally, eosinophil infiltration – a common characteristic of asthma – has been observed in the airways of some COPD patients (Chalmers et al., 2002; Nakawah et al., 2013).
Highlighting the pathological and functional overlap between diseases, patients can be found to have components of both diseases, which is particularly the case in the elderly. It has been reported that dual diagnosis of the two diseases increases with age, potentially reaching above 50% in patients over 80. This includes patients who are considered to have asthma with a COPD component, or COPD with features of asthma (Nakawah et al., 2013; Soriano et al., 2003).
The treatment landscape for respiratory disorders has traditionally been dominated by small molecule therapies that aim to treat the disease symptoms, rather than the cause. This means that treatment options can be diverse in terms of their targets and mechanisms of action. This is most notable in cystic fibrosis, where patients may be prescribed a combination of drugs from several treatment categories, including mucolytic agents, bronchodilators and antibiotics. The COPD and asthma treatment landscapes employ similar symptomatic treatments, including bronchodilators and inhaled corticosteroids (ICS).
However, over recent years there has been a strong trend in the industry of focusing on targeted biologic therapies that act on molecular components of the underlying disease pathophysiology, with the hope that they will offer disease-modifying alternatives. Although this trend has been most prominent in therapy areas such as oncology, it is now beginning to emerge in the respiratory disorder treatment landscape.
There are a number of entrenched, commercially successful products in the respiratory disorder market, such as Advair and Symbicort, which offer potent symptom relief, but there is also a high unmet need in patients whose symptoms are not controlled by standard therapies, as well as for treatments that are disease modifying, and proven to reverse disease progression. This is particularly pressing in both asthma and COPD.
As the scientific understanding of the cellular and molecular mechanisms underlying respiratory disorders has grown, this has allowed for the identification of novel targets for therapeutic intervention, particularly in relation to the inflammatory response characteristics of COPD and asthma. This has allowed for more innovative product development in a therapy area that traditionally has witnessed only low levels of therapeutic innovation. Typically, advancements have tended to be incremental, such as improved dosing regimens.
A notable example of an innovative, first-in-class product to enter the market was Xolair (omalizumab), a recombinant humanized anti-IgE monoclonal Antibody (mAb), which was the first humanized therapeutic mAb to be indicated for asthma. It was approved by the FDA in 2003 as an add-on therapy for adults and adolescents aged 12 and over with moderate-to-severe allergic asthma, who have a positive skin test or in-vitro reactivity to a perennial aeroallergen, and whose symptoms are not adequately controlled with ICSs. Xolair was subsequently approved in Canada in 2004, in Europe in 2005, and in Japan in 2009. Furthermore, in 2009 the approval of Xolair was expanded to the treatment of severe asthma in children aged between six and 11 in Europe.
For a number of years, Xolair was the only targeted therapy indicated for the treatment of a specific asthma phenotype. The launch of the drug therefore addressed a significant unmet need for personalized therapy in asthma. Approximately 60% of asthmatics have allergic asthma and may therefore benefit from Xolair treatment. Only a minority of these patients has moderate-to-severe disease that is inadequately controlled with standard-of-care therapies, and is therefore eligible for treatment. Despite this, the drug has achieved blockbuster status, and although this can be attributed to a high annual cost of therapy, it is also reflective of how innovative drug development that targets unmet clinical needs can result in strong commercial outcomes.
More recently, the asthma market has benefited from the approval of two mAb therapies – Nucala (mepolizumab) and Cinqair (reslizumab), marketed by GlaxoSmithKline (GSK) and Novartis respectively. Nucala received FDA approval in November 2015 as an add-on maintenance treatment, and became the first interleukin (IL)-5 targeted treatment for patients with severe eosinophilic asthma. It was subsequently approved in the EU in December 2015.
IL-5 is a key element in the recruitment of eosinophils, which are heavily implicated in airway inflammation and the lung-tissue remodeling process, including fibrosis and airway thickening. Nucala has shown promise when targeted at specific subtypes of chronic severe asthma, characterized by high levels of eosinophils and frequent exacerbations (Halder et al., 2009; Nair et al., 2009). This therapy is also in Phase III development for COPD.
Following the approval of Nucala, Teva announced the FDA approval of Cinqair (reslizumab) in March 2016 – again as a maintenance treatment in severe asthma patients characterized by elevated levels of eosinophils. Both of these approvals were aimed at addressing the notable unmet need in the market related to severe forms of disease not controlled by standard treatment. Such patients may experience increased rates of exacerbations and hospitalization, and therefore place a significant burden on healthcare services. There were only limited alternatives for such patients prior to these approvals, and it is hoped that they will reduce the burden caused by severe respiratory disease.
Other examples of targeted biologics in development in the respiratory disorder pipeline, which will be hoping to emulate the success of Nucala and Cinqair, include AstraZeneca’s benralizumab, another IL-5-targeted drug; Regeneron Pharmaceuticals dupilumab, a first-in-class therapy that inhibits the activity of IL-4 and IL-13; and Roche’s IL-13-targeting lebrikizumab. This trend is a significant development in this therapy area, particularly in relation to asthma and COPD, which for years saw very little innovative product development.
It now appears that – following the trend set by other disease areas such as oncology – these indications will benefit from multiple innovative targeted therapies, aimed at specific patient phenotypes that were previously poorly served by available treatment. Clinically, this offers the hope that patients who have struggled to achieve symptom control with standard treatment will be able to do so with new therapeutic options. In addition, this could help alleviate the burden on healthcare providers, given the tendency for severe respiratory disease sufferers to be hospitalized.
Commercially, as seen with other similar classes of therapy in the industry – such as the aforementioned Xolair – drug developers may also benefit from strong revenue generated by these novel products. This is reflected in the significant investment big pharma companies such as GSK, AstraZeneca and Roche have made in this area of product development in recent years.
References
Athanazio R (2012). Airway disease: similarities and differences between asthma, COPD and bronchiectasis. Clinics; 67: 1335-1343
Chalmers GW, et al. (2002). Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma. Thorax; 57: 226-230
GOLD (2015). Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. Global Initiative for Chronic Obstructive Lung Disease. Available from: http://www.goldcopd.com [Accessed on July 29, 2016]
Halder P, et al. (2009). Mepolizumab and exacerbations of refractory eosinophilic asthma. The New England Journal of Medicine; 360: 973–984
Nair P, et al. (2009). Mepolizumab for prednisone dependent asthma with sputum eosinophilia. The New England Journal of Medicine; 360: 985–993
Nakawah MO, et al. (2013). Asthma, chronic obstructive pulmonary disease (COPD), and the overlap syndrome. Journal of the American Board of Family Medicine; 26: 470-477
Soriano JB, et al. (2003). The proportional Venn diagram of obstructive lung disease: two approximations from the United States and the United Kingdom. Chest; 124: 474-481