COPD Therapy Evolution: Industry Giants Vie for a New Blue Ocean

GSK Adds Fuel to the Fire for COPD.

On July 28, Hengrui Medicine announced a global collaboration with GSK worth up to $12 billion, featuring the core asset PDE3/4 inhibitor HRS-9821 and a one-time "package deal" of 11 innovative projects for overseas markets.

According to the agreement, GSK will first pay Hengrui Medicine 500 million US dollars as an upfront payment to obtain the global exclusive rights of HRS-9821 outside of mainland China.

This deal has pushed COPD into the spotlight. Once a track gradually gaining attention due to the monopoly of the traditional triple therapy (ICS/LAMA/LABA), it is now transforming into a blue ocean fiercely contested by giants, thanks to breakthroughs in new mechanism small molecules and biologics.

GSK's accelerated layout was hinted at long ago. Two months ago, its IL-5 monoclonal antibody, mepolizumab, received FDA approval for a new indication, becoming the second COPD biologic globally and the third new COPD therapy approved within a year. Meanwhile, just over half a month ago, Merck acquired Verona Pharma for $10 billion, bringing the first PDE3/4 inhibitor, Ensifentrine, into its portfolio.

Sanofi's IL-4Rα star drug Dupilumab has entered the arena with great strength, while AstraZeneca's TSLP antibody Tezepelumab is also eyeing the market aggressively. Many pharmaceutical companies in China are continuously striving to catch up, leading to an escalating competition in the entire COPD field.

In the past, the global COPD field was mainly monopolized by a few players such as GSK, AstraZeneca, and Boehringer Ingelheim. Nowadays, with more big pharmaceutical companies entering the fray, a "major battle" that will determine the COPD market landscape for the next decade has already begun.

The "Surprise" of Small Molecules

Small molecule drugs have always been regarded as the "elder statesman" of drug development, stable and reliable, but compared to the rapid development of large molecule drugs, they appear somewhat lagging in innovation.

This is also a current situation in the field of COPD. Here, small molecule drugs have always been the main players. Currently, the FDA has approved about 40 COPD drugs (mostly inhalation preparations). The most widely used in clinical practice are bronchodilators (β2 agonists and anticholinergics) and anti-inflammatory drugs (corticosteroids), primarily the two triple therapies: GSK's Trelegy Ellipta (fluticasone + umeclidinium + vilanterol) and AstraZeneca's BREZTRI (budesonide + glycopyrronium + formoterol).

These are mostly small-molecule drugs based on traditional mechanisms, primarily enhancing efficacy through combination therapies. More importantly, while these drugs are effective, there remains a significant amount of unmet clinical needs.

For example, although the highest-standard triple therapy can significantly improve lung function and reduce the frequency of acute exacerbations, approximately half of the patients still experience COPD acute exacerbations after receiving triple therapy; moreover, survey data shows that about 56% of patients are dissatisfied with maintenance treatment.

Until June 2024, Verona's Ensifentrine received FDA approval, becoming the first new mechanism inhalation formulation in 20 years — it achieves dual effects of bronchodilation and anti-inflammation through dual inhibition of PDE3/4.

Clinical data show that in two Phase III trials, Ensifentrine demonstrated statistically and clinically significant improvements in lung function measurements in patients with moderate to severe COPD; notably, Ensifentrine significantly reduced the rate and risk of moderate to severe COPD exacerbations (by 36%-43%), and was well-tolerated by patients.

Under the boost of efficacy, Ensifentrine rapidly gained market traction upon its launch. In the first quarter of 2025, Ensifentrine's net sales reached 71 million U.S. dollars, marking a 95% increase quarter-over-quarter.

More importantly, the greater potential of Ensifentrine is not to defeat traditional therapies as a replacement, but to provide additional clinical benefits on top of triple therapy. Currently, its combination with the highest market share LAMA drug has entered phase II clinical trials, and if successful, it may become the standard treatment for mild to moderate patients.

SeekingAlpha predicts that the annual peak sales of Ensifentrine will reach $2.1~3.6 billion. According to a research report by Jeffery, doctors expect Ensifentrine to capture over 20% of the market share.

The potential of the blockbuster product was fully revealed, thereby gaining the favor of Merck.

In fact, before Verona, the industry had already conducted numerous explorations on PDE inhibitors, but this path was full of obstacles. Both single PDE4 inhibitors and early PDE3/4 dual inhibitors faced significant challenges, and GSK also stumbled in this area.

Faced with the "surprise" brought by Ensifentrine, as a veteran player in the respiratory field, GSK naturally does not want to miss such an opportunity. This might be the core reason why it chose to follow Merck's lead and bring in HRS-9821 from Hengrui Medicine through BD, especially since the latter is considered to have the potential to be the best-in-class PDE3/4 inhibitor.

Besides Hengrui Medicine, domestic enterprises such as China Biologic Products are also striving to gain a foothold in this field.

Next Match Point

As small molecules break new ground, biologics are also reshaping the treatment logic of COPD through "precise stratification."

Since the pathogenesis of COPD is relatively complex and has not been fully elucidated, chronic inflammatory response is considered one of the most important pathogenic mechanisms. Current research focuses more on eosinophilia mediated by the Th2 pathway.

Studies show that 20% to 40% of COPD patients exhibit the eosinophilic phenotype, and eosinophils are closely related to acute exacerbations of COPD. Therefore, inhibiting the development of type 2 inflammation has become a popular research direction for COPD. Monoclonal antibodies targeting pathways such as IL-4Rα, IL-5, and TSLP have become the new battleground.

Among them, both IL-5 monoclonal antibody and IL-4Rα monoclonal antibody act on the Th2 pathway. The former blocks the interaction between IL-5 and its receptor, reducing the maturation and activation of eosinophils, thereby inhibiting type 2 inflammatory responses. The latter acts at a core position in the Th2 pathway, not only inhibiting the release of IL-5 and chemokines to suppress eosinophil migration, but also blocking the signal transduction pathways of IL-4 and IL-13 to inhibit type 2 inflammation.

Sanofi's Dupilumab (IL-4Rα) Takes the Lead, Approved for Add-on Maintenance Treatment in Uncontrolled COPD Patients Characterized by Elevated Blood Eosinophil Levels. In 2024, two Phase III trials (BOREAS/NOTUS) showed that Dupilumab reduced moderate to severe exacerbation rates by 30%-34%.

GSK's Mepolizumab (IL-5) follows closely, engaging in direct competition with Dupilumab. Although it lags behind Dupilumab in key efficacy data, GSK believes it holds potential differentiating advantages.

Firstly, the dosing frequency is once a month, while Dupilumab requires dosing every two weeks; secondly, the potential range of applicable patients is broader. GSK's Phase 3 trial covered a wider variety of patient types, including COPD patients with chronic bronchitis, emphysema, or both, whereas Dupilumab does not include patients with emphysema alone.

However, from the peak sales forecast, the £500 million peak for mepolizumab is significantly lower than BMO's $2.5 billion peak forecast for dupilumab in the COPD field.

Compared with targets such as IL-4R, TSLP is located more upstream, at the top of multiple inflammatory cascade reactions, and is an important driver of type 2 inflammation, acting as a pro-inflammatory cytokine in various types of inflammatory and immune diseases.

Currently, the development of TSLP-targeted tumor indications is relatively concentrated, with the fastest clinical progress seen in asthma indications. Due to the association between COPD and asthma, research on the use of TSLP monoclonal antibodies for COPD treatment is also gaining significant attention.

Currently, there is no TSLP monoclonal antibody approved globally for the treatment of COPD. The fastest progressing in clinical trials are Amgen and AstraZeneca's Tezepelumab, Biosion's BSI-045B, Novartis' Ecleralimab, and AllTrust Bio's QX-008N, among others.

Not only TSLP, but also IL-4R and IL-5, the requirements for patients' eosinophil levels limit the benefiting population to 20~40% of COPD patients. Other patients need more effective therapies. The most promising one was IL-33 because it targets the largest patient group (non-type 2 inflammation patients, accounting for about 60-70% of severe COPD patients).

However, the biggest variable also comes from the IL-33 target.

Exploring More in the Thorns

The global patient population with COPD is extremely large, with over 500 million patients worldwide (nearly 100 million in China), 35% of whom have moderate to severe cases, resulting in 3 million deaths annually.

According to the latest report by GlobalData, driven by the launch of the world's first COPD biologic and other pioneering pipeline drugs, the COPD market in seven major developed countries (the United States, France, Germany, Italy, Spain, the United Kingdom, and Japan) is forecasted to grow from $11.5 billion in 2023 to $30.8 billion in 2033.

As mentioned earlier, this track, which was once monopolized by the traditional triple therapy (ICS/LAMA/LABA) and gradually became highly competitive, is now transforming into a blue ocean fiercely contested by giants due to breakthroughs in new mechanism small molecules and biologics.

However, high returns come with high risks. Since the beginning of this year, two major COPD drugs have failed in clinical trials.

First, Sanofi and Regeneron's IL-33 monoclonal antibody Itepekimab. Itepekimab was highly anticipated, with previous predictions estimating the drug’s sales to reach $3.5 billion.

However, at the end of May, Regeneron announced that one of the two Phase III COPD studies of Itepekimab was successful while the other failed.

AERIFY-1 Trial Tests Itepekimab in Poorly Controlled Former Smokers, Meeting Primary Endpoint: At 52 Weeks, Biweekly Itepekimab Injections Reduced Moderate to Severe Acute Exacerbations by 27% Compared to Placebo; This Reduction Was 21% for Patients Dosed Every Four Weeks. The Company Described This as a "Clinically Meaningful Benefit."

However, the AERIFY-2 trial failed to achieve the same goal, despite observing benefits in the early stages of the trial. At week 52, the acute exacerbation rate in patients receiving Itepekimab every two weeks was reduced by only 2%. Although the reduction was 12% in patients dosed every four weeks, it still did not reach the threshold for the primary endpoint.

The market generally expects that Itepekimab is unlikely to be approved without further testing.

Then on July 21, Roche's Astegolimab achieved "one success and one failure" in two clinical trials. The Phase IIb ALIENTO study met its primary endpoint, showing that Astegolimab administered every two weeks significantly reduced the acute exacerbation rate by 15.4%. However, the Phase III ARNASA study only reduced it by 14.5%, failing to reach statistical significance.

This outcome is identical to the experience of Itepekimab. Next, all eyes will be on how AstraZeneca's tozorakimab performs in clinical trials.

These setbacks also reflect the significant scientific and clinical challenges faced in the development of new drugs for heterogeneous and complex pathological diseases like COPD.

Pharmaceutical companies need to explore more in the thorns, including but not limited to the research of new targets, combination therapy, the game of long-acting formulations, and so on.

In any case, the essence of the COPD market transformation lies in the shift of treatment logic from a "one-size-fits-all" approach to precision targeting. The choices made by industry giants like GSK have already indicated the direction, and Chinese pharmaceutical companies, with their keen sense for drug targets and breakthroughs in manufacturing processes, have also secured their tickets to compete.

Next, it remains to be seen who can prove themselves with real strength in this chaotic battle.

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