INTRODUCTION
Asthma is perhaps the most common chronic disease encountered in outpatient pulmonary practice. The global disease burden of asthma is substantial, and the scenario in India is not different. Estimates reveal that 37·9 million Indian citizens are asthmatic, a number that matches 55% of the UK population.[1] The disease burden of asthma in India outweighs the number of people with HIV infection or tuberculosis. The phase 3 International Study of Asthma and Allergy in Children revealed that 7% of Indian children were wheezers, with a substantially greater occurrence of up to 10–20% in certain geographic pockets.[2] Asthma is perceived as an easily diagnosable and treatable disease with many efficacious agents available for therapy. However, despite the availability of effective therapy, community-level studies conducted in various geographic locations have revealed that only a small percentage of asthmatics in Asia achieve guideline-defined asthma control.[3,4] The economic burden and health-related disability of poor asthma control are substantial, both in terms of quality of life and utilisation of healthcare resources.[5]
Biologic agents have revolutionalised the way pulmonologists look at and treat asthma. A combination of inhaled steroids (ICSs) with long-acting beta two agonists (LABAs) has become more or less the standard of care in asthma. Many ICS–LABA combinations are commercially available, although recent reviews and systematic reviews[6,7] have highlighted the advantages of formoterol-fluticasone therapy. Patients with severe asthma who remain uncontrolled despite a high dose of ICS–LABA merit therapy with biological agents.[8] With the approval of multiple biological agents to treat severe asthma, decision-making on the choice of an upfront agent has been challenging. Without the availability of head-to-head trials, knowing which biologic to initiate first in a patient eligible for multiple options can be daunting. Some patients with severe asthma do not achieve sufficient control of their disease with the initial biological treatment and might need a shift of drug. The present review attempts to spell out the available biological agents for asthma therapy in India, the relative merit and demerit of each, attitudes of Indian patients to biological agent therapy, real-world efficacy of biological agents, choice of agent in severe asthma with overlapping phenotypes and practical prescription recommendations to Indian pulmonologists who contemplate biological agent therapy for severe asthma.
ATTITUDES OF INDIAN PATIENTS TO ASTHMA THERAPY
Researchers are increasingly realising the importance of patient attitudes to prescribed drugs and therapeutic agents as crucial aspects of treatment adherence, the success of medications, and overall disease control. The Asia–Pacific Asthma Insight and Management (AP-AIM) study[9] was undertaken to decode multiple facets of asthma-like symptom burden, medication preference, disease control, exacerbation rate, etc. across eight Asian countries including India. Four hundred patients hailing from various geographic locations of the country were evaluated as a part of this study. A substantial majority (91%) of Indian asthmatics believed that their disease control was optimal, whereas none of them met the control criteria when evaluated by objective measures. Up to two unscheduled casualty visits a year was a routine norm for Indian patients, and they believed that this does not breach the definition of optimum control. Short courses of oral steroids (>10 times a year) were consumed by 85% of Indian asthmatics. Only 36% of Indian asthmatics used controller inhalers with a majority preferring the oral route of asthma medication.
As previously mentioned, treatment success in asthma revolves around patient beliefs, their acceptance of the prescribed medications, and subsequent adherence to treatment regimens. Hence, identifying the attitudinal determinants of asthma control is of paramount importance, especially when it comes to therapy with expensive agents like monoclonal antibodies. The authors of an Asian study[10] have stressed the need for individualisation of pharmacotherapy (broadly adhering to guidelines) tailoring to the needs of patients with various attitudinal clusters. There has been a paucity of data on the attitude of asthmatic patients toward therapy with monoclonal antibodies. We have previously undertaken the ARTWORK study[11] which looks at the acceptance and results of therapy with omalizumab in real-world South Indian settings. This was a retrospective study on patients with inadequate asthma control as per GINA guidelines. Patients with persisting poor asthma control despite correction of modifiable factors who were deemed suitable to receive omalizumab were evaluated with their attitudes toward acceptance or refusal of this drug and the reasons for opting out were noted. The patients who received omalizumab were followed up to determine the results of treatment and duration of adherence to therapy. It was noted that two-thirds (35/51 patients) who were candidates for omalizumab therapy chose to avoid this drug. The reasons for opting out included an erroneous perception of optimal asthma control, the cost of therapy, and concern about adverse effects. Patients took omalizumab for a median duration of 6 months only. [Figure 1] Improved asthma control and decreased frequency of exacerbation were noted in all patients during therapy which persisted during the 6-month follow-up after cessation of therapy.
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Figure 1: Reasons behind Indian patients opting out of therapy with biological agents. Source of data – reference 11. Figure constructed by authors
When to initiate biological in severe asthma
“Severe asthma” describes asthma that is dependent upon high-dose inhaled corticosteroids (ICSs) plus a second controller (and/or systemic corticosteroids) to maintain symptom control, or which remains “uncontrolled” despite these therapies.[12] Once comorbidities have been addressed and excluding those patients who are poorly adherent to inhaled therapy, the prevalence of severe asthma is estimated at 3.7% of the asthma population.[12] GINA guidelines have recommended monoclonal antibodies as the preferred agents for step five asthma therapy. The care of patients with severe asthma has substantially changed over recent years, with monoclonal antibodies being increasingly available and studied in this category of asthmatics. Omalizumab has been the only approved anti-asthma monoclonal antibody for almost a decade. Omalizumab has been specifically approved for patients with severe allergic asthma, but case reports[13] and series have suggested benefits even in non-atopic asthma. However, subsequently, six biologic therapies reporting positive results in phase 3 trials have become commercially available.[14] As mentioned in an earlier section, the perspective of individual patients also should be given due consideration in addition to guidelines before contemplating biological agent therapy. [Table 1] summarises the various aspects of Food and Drug Administration (FDA)-approved biological agents for asthma therapy.
Table 1: Monoclonal antibodies commercially available for severe asthma treatment in India. Source of data from references 21, 22. Table created by authors
Potential for overuse and underuse of biologicals
As evident from the ARTWORK study,[11] there is a huge potential for overuse as well as underuse of monoclonal antibodies in asthma. Of the 560 patients with uncontrolled asthma, the systematic evaluation revealed that 480 patients had simple correctable factors that led to poor asthma control, like non-adherence to inhalers, persistent triggers, and lack of address of comorbidities that can worsen asthma control. In the absence of a rigid focused evaluation, these 480 patients might have been erroneously labelled as severe asthmatics and could have been considered for unnecessary therapy with biological. The finding substantiates that a large chunk of uncontrolled asthmatics has modifiable factors that can improve asthma control and do not need high-intensity treatment. The importance of adhering to a checklist in cases of uncontrolled asthma cannot be overstressed.
At the other end of the spectrum, a large number of “true” severe asthma patients who qualify for and who potentially benefit from monoclonal antibody therapy ultimately end up not receiving the agent. In India, this may be due to various reasons like the poor perception of asthma control, economic constraints, preference against a parenteral agent, concern for adverse effects, need for prolonged therapy, etc. The fact that two-thirds of the eligible patients do not receive the agents may be viewed as a lost therapeutic opportunity and focus may be given to providing information and motivating these patients in a specialised severe asthma clinic.
Phenotyping severe asthma – challenges in India
Phenotypic assessment of patients is a key step in patients with severe asthma who are being considered for monoclonal antibodies. A careful phenotypic characterisation requires focused clinical and functional evaluation, topped up by the measurement of biomarkers of type 2 asthma (serum IgE levels, blood eosinophil count, FeNO, etc).[15] The phenotype-driven first choice of a given biologic is usually associated with a satisfactory therapeutic response. However, some patients with severe asthma do not achieve sufficient control of their disease during the initial biologic treatment, thus requiring a therapeutic shift.[16] [Table 2] summarises the techniques for phenotyping in severe asthma with the merits and demerits of each.
Table 2: Common biomarkers used for phenotyping severe asthma with their relative merits and demerits. Source of data from references 14, 15, 18, 20. Table created by authors
The practical challenges involved in the phenotyping of severe asthma faced by Indian pulmonologists are manifold. The high prevalence of helminthic disorders has been postulated to be a cause of falsely elevated serum IgE levels and peripheral blood eosinophils. The nomograms for non-allergic Indian individuals are also less clearly known. Ongoing studies might resolve these challenges. Sputum eosinophil estimation is cumbersome, and very few specialised centres are confident in routinely utilising and interpreting this test. The availability of FeNO testing is also limited in India. Serum periostin estimation remains more or less a research tool and is not commercially available. All these caveats render flawless phenotyping of severe asthma a challenging exercise in India and clinicians resort to a combination of clinical characteristics with limited tests for phenotyping and decision of biological therapy.
Choice of an agent in severe asthma with overlapping phenotypes
At the time of preparation of this manuscript, the three monoclonal antibodies commercially available in India for the treatment of severe asthma are omalizumab, mepolizumab, and benralizumab. Many patients with severe asthma have both allergic and eosinophilic phenotypes, thereby making them candidates for therapy with an anti-IgE agent (omalizumab) or anti-IL 5 agents (mepolizumab or benralizumab). Guidelines and consensus statements[17] propose patient stratification for available biologic therapies mainly on clinical end points, allergy tests, IgE levels, and blood eosinophils. There are insufficient data for other biomarkers such as periostin or FeNO. The optimal cut-off level of eosinophils for initiation of anti-IL-5 is still subject to debate. A minimal level of 150 per mm3 is often utilised for mepolizumab based on pivotal trials,[18] but NICE has proposed a higher level. A blood eosinophil count of 400 per mm3 is considered to be the threshold for the initiation of reslizumab.
Practical considerations for clinicians before they choose a particular biological agent in a severe asthmatic with overlapping phenotype are many.[19,20] [Figure 2] depicts some considerations for the choice of biological agents in Indian practice settings.
Figure 2: Practical aspects to be considered by clinicians on the choice of biological agents for severe asthma therapy. Figure designed by authors
- Age of the patient – omalizumab is approved for any patient aged 6 years or above, whereas benralizumab is approved only for patients above 18 years.
- Associated allergic manifestations – patients with nasal polyposis and chronic rhinosinusitis have a good response to omalizumab. Patients with atopic dermatitis have a good response to omalizumab and dupulimab (not marketed in India as of now). Mepolizumab has been approved by the FDA for eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome, etc.
- Patient expectations of treatment benefit – the specific aspects of asthma control that the patient expects to improve are of prime importance in the choice of a biological agent. Patients may expect benefits like a reduction in exacerbations, sparing of systemic steroid usage, improvement in lung function, etc., In the absence of head-to-head trials between biologics, the best reduction in exacerbation rates and maximal steroid-sparing effect is afforded by benralizumab.[21,22]
- The convenience of therapy – anti-IL 5 agents are commercially available in a pre-filled syringe which makes administration easier for the caregiver, as opposed to omalizumab which comes as a dry powder and needs time to be reconstituted. Omalizumab has the additional limitation that dose and frequency of administration vary based on patient factors (pretreatment serum IgE levels and body weight) whereas the dose of mepolizumab and benralizumab is fixed. After the three initial induction monthly doses, benralizumab offers the convenience of a once-in-two-month dosage, which is a distinct advantage.
- Expenses incurred with therapy – in a country like India where a major fraction of patients have to pay out of pocket for medical expenses, the agent with the least expense has a definite edge. Omalizumab has the advantage that generic biosimilar preparations are available in the market.[23]
Switching of biological agents
The phenotype-driven first choice of a given biologic is usually associated with a satisfactory therapeutic response. However, some patients with severe asthma do not achieve sufficient control of their disease during the initial biological treatment, thus requiring a therapeutic shift.[16] This is especially true for patients treated with omalizumab, which has been for a long time the only approved anti-asthma monoclonal antibody.[24] Several studies have shown that allergic patients with severe asthma, who are not responsive to omalizumab, can be successfully switched to mepolizumab.[25–27] Literature referring to an eventual therapeutic shift from omalizumab to benralizumab is much less in number.[28,29]
An Italian study[28] reported 20 allergic patients with severe eosinophilic asthma, unsuccessfully treated with omalizumab. These subjects were then switched to benralizumab and assessed for at least 1 year for changes in disease exacerbations, symptom control, oral corticosteroid intake, lung function, and blood eosinophils. After 1 year of treatment with benralizumab patients experienced significant improvements in asthma exacerbation rate (P < 0.01), rescue medication need (P < 0.001), asthma control test (ACT) score (P < 0.05), forced expiratory volume in the first second (FEV1) (P < 0.05), and blood eosinophil count (P < 0.0001). Furthermore, for the end of omalizumab treatment, the score of sino-nasal outcome test-22 (SNOT-22) significantly decreased after therapy with benralizumab (P < 0.05). The study concluded that the pharmacologic shift from omalizumab to benralizumab can be a valuable therapeutic approach for allergic patients with severe eosinophilic asthma, not adequately controlled by anti-IgE treatment. Benralizumab has also been reported to be effective in patients who are unresponsive to both omalizumab and mepolizumab.[29]
The mechanism of action of benralizumab differs from that of mepolizumab as benralizumab binds to the alpha subunit on IL-5 receptors, inhibits IL-5 cytokines from binding, and leads to antibody-dependent cell-mediated cytotoxicity of eosinophils via natural killer cells.[21,30] This dual response to benralizumab treatment may be responsible for the consistently marked reduction in blood eosinophil levels and improvements in exacerbation rates reported by phase 3 trials for benralizumab in severe eosinophilic asthma.[31,32] Additionally, in a phase 3 trial of mepolizumab, blood eosinophils were not depleted to the same extent as reported with benralizumab herein.[18] Benralizumab improves lung function and exacerbation rates in patients with severe eosinophilic asthma regardless of atopic status and serum IgE concentrations.[33]
Switching of biological agents is being increasingly reported in severe asthmatics. The largest body of published evidence to date comes from the US CHRONICLE study. Data from the International Severe Asthma Registry and the US CHRONICLE Study[34] suggest that 10.8% (384/3531) of patients who used biologics for asthma switched the agent. The most frequent first switch was from omalizumab to an anti–IL-5/5R (49.6%; 187/377). The most common subsequent switch was from one anti–IL-5/5R to another (44.4%; 20/45). Insufficient efficacy and/or adverse effects were the most frequent reasons for stopping/switching. Patients who stopped/switched were more likely to have a higher baseline blood eosinophil count and exacerbation rate, lower lung function, and greater healthcare resource utilisation. Substantial published data on biological agent switching in severe asthma is lacking from India.
The treatable trait model in asthma care
Asthma is a complex and heterogeneous disease. Traditionally, clinical guidelines have advocated a stepwise approach to pharmacotherapy of asthma, but there is an increasing realisation that asthma therapy requires a more individualised and precise management approach. To this end, a management strategy based on the so-called “treatable traits” has been proposed[35] which is a direct extension of the concept of personalised medicine in asthma care. The traditional treatment model lacks an objective assessment of underlying biological processes, and there is a potential for treatment to be escalated to higher doses in a futile fashion, or further treatments added in, without full consideration of alternative explanations for symptoms in a patient-centric manner. This can expose patients to adverse side effects from potentially ineffective or potentially harmful treatments, such as high doses of ICSs or oral corticosteroids (OCSs), particularly in patients with low type 2 inflammation markers or with misattributed symptoms (e.g., vocal cord dysfunction). Stepwise treatment can also reduce cost-effectiveness and lead to increased time to reach the best treatment option because each step up or down may take weeks or months to assess effectiveness. Finally, both patients and healthcare professionals tend to overestimate the level of asthma control due to a lack of symptom perception or acceptance that symptoms are a part of life, but symptom-based definitions of control may also be overly rigid compared with patients’ views. There are limited data currently available on the prevalence of treatable traits in different populations, but data for some traits can be derived from existing observational studies and disease registries. The current treatable trait model in asthma care has proposed[36] traits under three broad domains, viz., pulmonary, extrapulmonary, and behavioural subheadings, and advocates a systematic effort to identify and address each. [Table 3] shares the various targetable treatable trains in asthma care in short. This approach offers an exciting and individualised strategy for asthma care that has the potential to revolutionalise the way physicians institute pharmacotherapy in asthma.
Table 3: Common treatable traits in severe asthma, their identification markers, and focused therapeutic options. Data sources from references 38 and 39. Table created by authors
The practical way forward
Considering the lacunae in evidence, uncertainties in response in an individual patient, and practical challenges at a grass root level, an Indian pulmonologist needs to adopt an individualised and sufficiently redundant approach to monoclonal antibody therapy in severe asthma, utilising published evidence and guidelines as a launching platform. Perspectives of the individual patient need to be sought for and respected when it comes to assessing the need for initiation of biologicals, choice of agent, and expected goals of treatment. Shared decision-making between the patient and doctor regarding the expected goals of therapy is of paramount importance and has to match with realistic outcomes. The authors propose a treatment paradigm [Figure 3] that may be utilised for the institution of monoclonal antibodies, choosing of an agent, and follow-up of treatment results which may be meaningful in Indian practice settings. It may be stressed that with growing Indian experience and evidence, this paradigm might undergo revisions and sophistication for the better.
Figure 3: A suggested practical algorithm for selection and follow-up of monoclonal antibody therapy in severe asthma for Indian patients. Data source from references 19, 20, 24, 37
CONCLUSIONS
Severe asthma constitutes a minority of asthma patients encountered in clinical settings but accounts for a large proportion of healthcare utilisation. The availability of monoclonal antibodies has opened a new door for the treatment of these severe asthmatics and has provided excellent clinical results in properly selected patients. With the availability of more and more molecules, the choice of an agent for upfront therapy might pose a challenge. Careful attention to the clinical profile of the patient, targeted investigations of the phenotype and endotype of the individual, and a thorough knowledge of the available evidence should assist in decision-making as to the choice of the agent. The cost of therapy remains a stumbling block for many Indian patients. Finally, it may be recollected that pharmacotherapy is only one aspect of asthma management, and a focus on a treatable traits approach might provide substantial benefits. Ongoing research is expected to improve understanding and simplify the practice in this arena.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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