Will Severe Asthma Be the Next Hot Antibody Drugs (I)

1. Will Severe Asthma Be the Next Hot Antibody Drugs (I)? About Omalizumab Omalizumab was first FDA approved in 2003 to treat adults and children 12 years of age and older with moderate to severe persistent allergic asthma which is not controlled by inhaled steroids. Since its U.S. approval, more than 200,000 patients older than 12 with allergic asthma have been treated. In August 2017, CFDA officially approved Novartis Tall® (Omalizumab) for the treatment of moderate to severe persistent allergic asthma, which means that China's asthma treatment has entered the era of antibody drugs. Then in September 2018, a new prefilled syringe formulation of this drug was approved by the FDA. Omalizumab has been listed for 17 years, and in 2016 brought Novartis nearly $ 800 million in annual sales. It is estimated that there are about 340 million asthma patients in the world, and the asthma drug market is about 16 billion US dollars and will continue to grow. The role of antibody drugs in the treatment of asthma, especially severe uncontrollable asthma, is becoming more and more important, and its market share will also increase. Facing the complicated immune system and asthma pathology, which targets

2. are more likely to become the next market contenders? About Asthma Asthma is a chronic inflammatory disease of the respiratory tract. The pathogenesis is more complicated. It is generally believed that it is caused by genetic and environmental factors. The main features of the disease are airway hypersensitivity, reversible airflow obstruction, bronchospasm muscle spasm, and airway inflammation. Common symptoms include wheezing, difficulty breathing, coughing, and chest tightness. The 2014 Global Asthma Report shows that the incidence of asthma is about 4.3%, which means that about 334 million people worldwide have asthma of varying degrees. It is expected that by 2025, this number will increase by 100 million to 434 million. Asthma imposes a great financial burden on society and individuals. It is estimated that the annual expenditure of asthma in advanced economies accounts for 1% to 2% of their total medical expenditure, which is higher than the sum of tuberculosis and AIDS. The Market Share of Asthma The treatment of asthma generally follows the step-by-step treatment guidelines of the Global Initiative for Asthma (GINA). Commonly used drugs include inhaled / oral glucocorticoids (ICS / OCS), leukotriene receptor antagonist (LTRA), long-acting β2 receptor agonist (LABA), short-acting β2 receptor agonist (SABA), Long-acting muscarinic receptor antagonist (LAMA), theophylline, etc. Antibody drugs have also been included in treatment guidelines since 2005. Due to the large number of patients and the long course of illness, asthma drugs have always been the mainstay of respiratory system drugs. The global asthma drug market in 2022 is likely to reach US $ 22 billion. From the perspective of drugs, long-acting β2 receptor agonists + glucocorticoid combined inhalation (LABA + ICS), or both single-use drugs dominate the market, accounting for almost half of the market. Considering that there are some ultra-long-acting β2 receptor agonists (ultra-LABA) that are used once a day in the research and development, the market position of these drugs will be further consolidated in the next five years. LAMA occupies the second place in the market (18%). As a commonly used rapid asthma relieving agent, SABA can account for approximately 6.5% of

3. the market. As the classic combination of LABA + ICS faces patent expiration and other issues, new combination dosage forms such as LAMA + LABA, LAMA + LABA + ICS and other new combinations run into the market to replace classic combination. An obvious trend is the rapid rise of antibody drugs. Although there are only four asthma antibody drugs in the global market, it is certain that this proportion and market share will continue to grow rapidly. It is expected to reach 2.2 billion US dollars in 5 years. Antibody drugs: hope for patients with severe uncontrollable asthma Most asthma patients can be well controlled under the existing treatment guidelines, but about 5% to 10% have severe or uncontrollable asthma. However, the medical expenses of this small group of patients can account for more than 60% of the entire asthma treatment expenditure, because the deterioration rate and hospitalization rate of this part of the patients are relatively high, occupying more outpatient and emergency resources. Individually, patients with severely uncontrollable asthma spend more than type 2 diabetes, stroke, or chronic pulmonary obstruction (COPD). The following factors have led to the limitations of existing guidelines for the treatment of severe asthma: First, the curative effect is limited. Patients with mild to moderate asthma can be well managed according to the guidelines, but the mortality and morbidity of severe asthma patients have not been effectively improved. Second, adverse reactions. Inhaled drugs have good safety record, and oral drugs should be more noticeable. For example, oral glucocorticoids are more likely to cause systemic adverse reactions and potential morbidity; theophylline has a narrow therapeutic window and poor tolerance. Third, the patient's compliance is poor. It is estimated that approximately 50% of children and 30-70% of adults cannot strictly follow the treatment regimen of the asthma guidelines. There are many reasons for this, such as improper use of inhalants, complicated treatment plans, and patients' concerns about adverse reactions. Fourth, there are comorbidities. Many asthma patients have obesity, cardiovascular disease, allergies, smoking and other comorbidities, which bring more challenges to treatment. Usually, comorbidities and asthma form a vicious circle.

4. Because antibody drugs directly target the immune mechanism of asthma, it has brought hope to many severely uncontrollable patients. In order to better understand the targets of antibody drugs, let's first understand the inflammatory mechanism of severe asthma. The inflammatory response of asthma is very complicated, involving a series of immune cells and inflammatory molecules in the respiratory cavity. Triggering of allergic asthma begins when respiratory epithelial cells secrete interleukins 25, 33 (IL-25, IL-33) and thymic stromal lymphopoietin (TSLP) after exposure to allergens, thereby activating dendritic cells (DC). The immunogen is presented to helper T cells (Th0) after DC treatment, and the latter secretes IL-4 to activate Th2 helper cells. Th2 cells are activated to release more IL-4 and IL-13, thereby promoting B cells to produce immunoglobulin E (IgE). IL-4 and transforming growth factor β (TGFβ) secreted by Th2 cells can also activate Th9 helper cells to secrete IL-9, thereby promoting the growth of mast cells. Mast cells bound by IgE can bind antigens, causing the cells to degranulate and release a large amount of chemical mediators, such as histamine, prostaglandins, leukotrienes, etc., which induces the contraction of bronchial smooth muscle and further stimulates the inflammatory response. Th2 cells can also secrete IL-5 to ensure the survival and growth of eosinophils. In addition, Th17 helper T cells are an important role in the pathogenesis of non-eosinophilic asthma, which can produce IL-17 to recruit and expand neutrophils. To be continued in Part II…