In 2023, the pharmaceutical industry will mark 20 years since Xolair, an anti-IgE antibody, became the first biologic approved to treat asthma. Since then, the US FDA, EMA, and other agencies have approved several biologic antibodies targeting the inflammatory cytokines IL-4, IL-13, IL-5, and others for asthma.
Approaches like bronchodilator inhalers focus on treating both asthma and chronic obstructive pulmonary disease (COPD). The same, however, is not true for therapeutic biologics. While the pharmaceutical landscape for asthma has several approved biologics, in stark contrast, the COPD environment has zero biologic approvals.
Today, approximately 384 million people around the globe have COPD and it is the third leading cause of death worldwide, the Global Initiative for Chronic Obstructive Lung Disease reports.
There are at least six different biologics being studied in Phase III trials in COPD clinical programmes around the world. Results from a Phase III trial with Sanofi and Regeneron Pharmaceuticals’ IL-4/IL-13 monoclonal antibody (mAb) Dupixent (dupilumab) are expected by mid-2023, followed by others.
While options like bronchodilator inhalers are available for COPD patients, these have limitations. “Bronchodilators are palliative in that they relieve the symptoms of the disease and do not target the underlying biology,” says Dr. Ian Adcock, Professor of Respiratory Cell and Molecular Biology at the National Heart and Lung Institute, Imperial College London.
“Biologics have the potential to impact disease-driving processes if we hit the right target in the right patient,” Adcock continues. Unlike bronchodilators, biologics also provide disease-modifying opportunities in COPD.
Biologics: From asthma to COPD?
Research has found cytokines are central to the regulation of an allergic phenotype, immunoglobulin E (IgE) response and cell-mediated inflammation. Biologics for asthma have even been classified as a Rapid Uptake Product in the UK, a status given to encourage greater adoption and growth of efficacious innovations.
“The advent of biologics in the treatment of severe asthma has revolutionised therapy for patients with evidence for Type 2 (T2) inflammation,” says Adcock. Type 2 inflammation is associated with high blood eosinophil counts and exhaled nitric oxide, and frequent exacerbations requiring antibiotic or steroid treatment or hospitalisation.
“In contrast, using this treatable trait (blood eosinophils and nitric oxide) has not proven successful in COPD,” Adcock shares. “Biologics targeting other aspects of COPD biology have also failed, [indicating] a huge knowledge and therapy gap in this disease.”
“However, despite around 20% of severe asthma patients having uncontrolled disease, only a relatively small fraction of these eligible patients are currently on biologics,” says David Pettigrew, CEO of digital therapeutics developer my mhealth, which has created asthma and COPD biologic solutions. With biologics being available to asthma patients, while those with COPD await approval, my mhealth has seen the differences in treatment approaches to the two conditions, says Pettigrew. It aims to help support patients and their clinicians in optimising their therapy and introduce more consistency in how patients are assessed for their treatment eligibility and its effectiveness.
In December 2021, AstraZeneca’s anti- thymic stromal lymphopoietin (TSLP) antibody Tezspire (or tezepelumab) became the latest biologic to be FDA-approved as an add-on treatment for patients with severe asthma without phenotype or biomarker limitations. Still, patients require an individual-led approach. For example, not all patients fitting the criteria of severe asthma with evidence of Type 2 inflammation have a good response. Tezspire is being studied in a Phase II COPD study (NCT04039113) that is expected to complete in March 2024. Data from this study has found that an elevated expression of TSLP—a pro-allergic cytokine—in serum and bronchial mucosa is evident in patients with COPD.
Better understanding of biologic efficacy
There have been several attempts to introduce biologics into the COPD space. In 2018, the FDA rejected the approval application for GSK’s Nucala (mepolizumab) in COPD. With three votes for and 16 against, the US Pulmonary Allergy Drugs Advisory Committee refused its use as an add-on treatment to inhaled corticosteroid-based maintenance. Nucala’s use was intended for patients based on their blood eosinophil counts. In reaching the decision, the committee stated that the demonstrable data indicated an inadequate risk-benefit profile to support the biologic’s approval.
AstraZeneca’s Fasenra (benralizumab)also failed to prove effective in Phase III trials in the same year. The trial did not achieve the primary endpoint of a statistically significant reduction of exacerbations in COPD patients.
However, in recent years, the understanding of the efficacy of biologics for COPD has evolved.
Biologic therapies for COPD are “also showing great promise,” says Pettigrew. But as these are still at the clinical trial stage, the company is currently working with its pharma partners and COPD userbase of 33,000 patients to help analyse available data.
“[Now], years of research are culminating in breakthroughs that may ultimately enable personalised therapies that go beyond just managing symptoms to actually treat the underlying disease”, saysNathalie Altermatt, media spokesperson at Roche. The Swiss pharma giant is running a Phase III trial (NCT05595642) with its anti-IL33 antibody astegolimab for patients with COPD, with an anticipated completion date in 2025, but a Phase II trial is expected to complete in 2024 (NCT05037929).
Despite the initial setback, AstraZeneca has proceeded with its Fasenra development programme, which is now being advanced in the Phase III Resolute trial (NCT04053634). Clinical evidence from the responder analysis of the Phase III programme shows that a subpopulation of COPD patients with elevated blood eosinophil counts combined with specific clinical characteristics had a reduction in exacerbations with Fasenra.
In addition to Tezspire, the British company is also advancing another biologic, an IL-33 mAb tozorakimab, in a Phase III Titania trial (NCT05158387) for COPD. Clinical evidence indicates tozorakimab can block IL-33 signalling through two distinct pathways—an ST2 receptor pathway involved in inflammation and a non-ST2 pathway linked to tissue remodelling through a reduction in inflammation and epithelial dysfunction.
Roche is also adopting the anti-IL-33 route, which has been shown to drive multiple types of inflammatory responses. “By blocking ST2, astegolimab has the potential to reduce the diverse types of inflammatory responses associated with disease exacerbation in patients with moderate-to-severe COPD,” Altermatt shares.
Have biologics for COPD arrived?
Not yet, but soon, industry players hope. With a flurry of results anticipated over the coming years, if the efficacy and safety of biologics for COPD are approved, we can expect to enter a new phase of treatment options for COPD. We may, however, have to wait longer than we first thought.
The turning point for biologics for COPD may centre on individual-led treatments. The first three clinical trials using anti-IL-5 antibodies in asthma failed as they selected all comers with no biomarkers or clinical features to stratify the patients into those most likely to respond, says Adcock. COPD research is also now exploring “the use of specific biomarkers to direct biological therapy to selected patients rather than all comers”, which Adcock continues to say “improves the numbers of people who will give a clinically significant response”.