While most asthma patients with a milder form of disease are well controlled, treatment options for severe, refractory asthma patients have long been the key unmet need in this space. The G7 asthma market is currently dominated by inhaled formulations such as long-acting beta2 agonist (LABA)/inhaled corticosteroid (ICS) fixed-dose combinations (FDCs), ICSs, short-acting beta2 agonists (SABAs), long-acting muscarinic antagonists (LAMAs), and LABAs, with approximately 83%1 of market share captured by these drugs. Though prescribed to patients across different severities of asthma from mild to severe, these drugs have been of limited use to treat exacerbations associated with severe, refractory asthma. Until 2003, the year when Xolair (Roche/Novartis’s omalizumab) was first launched, there was no biologic available in the market for the treatment of severe asthma. Xolair was the first biologic and injectable formulation launched for the treatment of asthma and was positioned to treat a niche patient segment suffering from moderate to severe persistent allergic asthma; today the drug enjoys around 7%1 share of the G7 asthma market.
Over the last few years, pharmaceutical companies and physicians have increasingly realized the heterogeneous etiology behind the disease and that there is no panacea available for all asthma patients. They have recognized the dire need of a more customized approach and targeted medications to treat each asthma patient individually, especially the severe ones who face more frequent exacerbations. Big Pharma is therefore focusing primarily on the development of drugs that cater to the unmet need in severe asthma. The majority of these drugs in late-phase development target different cytokines involved in the inflammatory cascade of asthma pathophysiology. The launch of Nucala (mepolizumab), an anti-IL-5 by GlaxoSmithKline in Q4 2015, the recent launch of Cinqair (reslizumab), another anti-IL-5 by Teva, and the forthcoming anticytokines in the asthma pipeline further prove this point. There are only a few biologic therapies in late-phase development targeting biomarkers other than cytokines.
Here are the few key biologic therapies that are under development for the treatment of severe, refractory asthma:
Benralizumab: Another anti-IL-5, benralizumab, a molecule from AstraZeneca, is under development for the treatment of severe, eosinophilic asthma patients who are 12 years old and above. Benralizumab is distinct from the currently marketed anti-IL-5s, Nucala and Cinqair, due to the fact that it specifically targets the alpha subunit of the IL-5 receptor, the binding site of IL-5, while the existing IL-5 antagonists aim to neutralize the circulating cytokine itself. Currently undergoing multiple phase III trials, benralizumab has already completed at least four phase III trials including the two pivotal trials SIROCCO and CALIMA2, with positive results in reducing exacerbations and improving FEV1, each compared with placebo. In phase III, benralizumab is under development as a 30 mg subcutaneous dose every 4 or 8 weeks while Nucala and Cinqair are each administered every 4 weeks, giving benralizumab an anticipated competitive advantage provided 30 mg every 8 weeks receives regulatory approval. Following its anticipated filing by the end of this year, the initial launch of benralizumab is expected in 2017.
Tralokinumab: Tralokinumab, a humanized monoclonal antibody (MAb) targeting IL-13, is also under development by AstraZeneca. Tralokinumab is currently in phase III with at least three key trials underway to evaluate its efficacy and safety in uncontrolled, severe asthma patients (> 12 years) with high periostin levels. The results from a phase IIb study suggest that tralokinumab subcutaneous injection every two weeks significantly improved FEV1 levels compared with placebo. However, no significant reduction in the number of exacerbations was observed.3 Tralokinumab is likely to be launched in 2019.
Dupilumab: Dupilumab is a humanized MAb being developed by Regeneron Pharmaceuticals in collaboration with Sanofi for the treatment of moderate to severe uncontrolled asthma patients. Dupilumab acts by blocking the alpha subunit of the IL-4 receptor, thus blocking/modulating the biological effects of two cytokines, IL-4 and IL-13. Currently in phase III trials, the drug has demonstrated promising efficacy through its significant reduction in exacerbations and improvement in lung function in phase II trials.4 A subcutaneous 200/300 mg once every two weeks dose is expected to launch for asthma in 2019.
QAW-039: QAW-039, also known as fevipiprant, is a CRTh2 antagonist being developed by Novartis for the treatment of severe, uncontrolled asthma. QAW-039 is an oral agent with once-daily dosing that is currently in phase III trials to evaluate its efficacy and safety in patients suffering from severe, uncontrolled asthma with and without a high eosinophil count. The phase II studies demonstrated mixed results for QAW-039. While in one phase II trial in patients with high eosinophilic levels the drug showed a statistically significant reduction in eosinophils compared with placebo at 12 weeks, there was no improvement in the ACQ7 or trough FEV1 ).5 In another phase II trial in 170 steroid-free patients to study the efficacy, safety, and pharmacokinetic profile of QAW-039, no significant improvement in lung function was observed and the primary end point (FEV1) was not met; however, a subgroup analysis of patients with FEV1 < 70% at baseline demonstrated a significant improvement of FEV1 compared with placebo.6 We expect QAW-039 to be launched in 2020 as the first CRTh2 antagonist to reach the market.
Given the strong unmet need in the severe asthma space, the trends in development, and positive clinical results demonstrated by multiple biologic therapies, this new emerging set of biologics will be a long yearned addition to the asthma armamentarium for pulmonologists and allergists, enabling them to adopt a customized approach to asthma treatment. The high price tags ensure that these biologics will be able to capture substantial share in the asthma market in years to come, despite their limited and overlapping target/eligible patient pool.
- Decision Resources Group. Asthma Disease Landscape and Forecast (2016)
- AstraZeneca press release, September 5, 2016
- Brightling CE, et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomized, double-blind, placebo-controlled, phase 2b trial. Lancet Respiratory Medicine. 2015; 3:692-701; clinicaltrials.gov NCT01402986
- Wenzel S, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomized double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016; 388(10039):31-44; clinicaltrials.gov NCT01854047
- Gonem S, et al. Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomized, double-blind, parallel-group, placebo-controlled trial. Lancet Respir Med. 2016; 4(9):699-707; clinicaltrials.gov, NCT01545726
- Erpenbeck VJ, et al. Data on the oral CRTh2 antagonist QAW-039 (fevipiprant) in patients with uncontrolled allergic asthma. Data Brief. 2016; 9:199–205; clinicaltrials.gov, NCT01253603