Better application of biologics may lead to asthma remission, prevention

Key takeaways:

• The 20-year cost of asthma will exceed $963 billion.
• Eosinophil counts may indicate who will best respond to mepolizumab.
• Toddlers at risk for asthma may benefit from omalizumab.

ANAHEIM, Calif. — The use of biologics for asthma will grow as physicians better define who will respond to specific treatments, according to a presentation at the American College of Allergy, Asthma & Immunology Annual Scientific Meeting.

The use of these drugs may even lead to remission and prevention for some patients, John Oppenheimer, MD, FACAAI, clinical professor of medicine at UMDNJ Rutgers, said during the presentation.

Costs and benefits

“Core asthma control is associated with increased exacerbation, reduction of health-related quality of life and increased health care utilization,” Oppenheimer said.

For example, he said, the 20-year cost of asthma will exceed $963 billion. Also, various studies have estimated the prevalence of uncontrolled asthma to range from 40% to 60% depending on the population and on how asthma control is defined.

“It’s very sobering,” he said. “We need to do a better job.”

Physicians need to acknowledge that not all asthmatics are the same, Oppenheimer said, adding that current guidelines do not recommend phenotyping until patients develop more severe disease.

“There are really data that we should be phenotyping earlier,” he said. “We have really interesting compounds to help us.”

Selecting the right biologic is key, Oppenheimer said.

“Our current pricing of biologics exceeds measures of cost effectiveness, and we need to really reduce them about 60% to make them cost-effective,” he said. “We need to figure out how to do this.”

However, he said, physicians could significantly improve the cost-effectiveness of biologics if they better understood indicators of who would be most likely to respond to therapy before it is initiated or if they could recognize early signs of response to therapy.

Oppenheimer cited a study of 1,247 patients with asthma who stopped their biologic therapy and 1,247 patients who continued their therapy for at least 18 months. After 6 months, 10.2% of those who stopped therapy and 9.5% of those who continued it had an increase in asthma exacerbations of 50% or more.

“It suggests that doctors are stopping the right patients,” he said.

Specifically, Oppenheimer continued, less than 40% of these patients consistently used their inhaled corticosteroids or long-acting beta agonists. Also, more than half of them did not have any exacerbations during the 6 months before index biologic use.

“It’s not that biologics are expensive,” he said. “Maybe we’re misusing them a little bit.”

Precision medicine matches treatments with patients, Oppenheimer continued.

“No one medicine is perfect for everybody,” he said. “We need to do a better job of using the right medicine for the right person.”

Choosing treatments

Oppenheimer cited a study that stratified patients treated with mepolizumab (Nucala, GSK) by eosinophil counts and found a 52% reduction in exacerbations among those with baselines of 150 cells/µL or higher and a 70% reduction among those with 500 cells/µL or higher.

“As you get below 150 [cells/µL], there really isn’t a very good signal of efficacy, so we can pick the person,” Oppenheimer said.

Another study found that patients with high levels of fractional exhaled nitric oxide, eosinophils and periostin had comparatively greater reductions in exacerbations with omalizumab (Xolair; Genentech, Novartis) than those with low levels of these biomarkers.

“We can somehow enrich the population likely to respond,” Oppenheimer said.

A third study stratified patients with asthma taking mepolizumab as responders, with greater than 50% reductions in exacerbations, and super-responders, who had no exacerbations and could stop using oral corticosteroids.

“Baseline characteristics associated with responder and super-responder status included nasal polyps, lower baseline Asthma Control Questionnaire [and] lower BMI,” Oppenheimer said.

Patients receiving maintenance oral corticosteroids and significantly lower doses of prednisolone also were more likely to be responders or super-responders.

At 16 weeks, Oppenheimer continued, the researchers could identify 80.8% of the patients who were going to be responders. At 24 weeks, that increased to 92.9%.

“Maybe we can stop biologics [for patients] that were not a responder or a super-responder earlier,” he said. “That would save money for the system.”

With more careful selection, Oppenheimer suggested, remission may be possible for some patients with severe eosinophilic asthma treated with mepolizumab.

Oppenheimer noted a study that included a three-component definition of remission (lack of oral corticosteroid use, lack of exacerbations, Asthma Control Test [ACT] score of 20 or greater) and a four-component definition that added an FEV₁ of 80% or higher.

The researchers found that 37% of the patients met the three-component definition, and 30% met the four-component definition.

At baseline, these patients generally had higher blood eosinophil counts, better ACT scores, better lung function, lower maintenance oral corticosteroid use and slightly lower rates of prior exacerbations.

“This would never have been achieved if we didn’t have biologics,” Oppenheimer said.

Potential prevention

Noting that exacerbations often occur in the fall because of viral infections, Oppenheimer cited a study of children aged 6 to 17 years with asthma who were treated with omalizumab or placebo for 4 months beginning 4 to 6 weeks before their return to school.

The omalizumab group had an 11.3% exacerbation rate, and the placebo group had a 21% exacerbation rate, for an odds ratio of 0.48 (95% CI, 0.25-0.92), which the researchers called a significant difference.

Among patients who experienced an exacerbation during the run-in phase, exacerbation rates included 6.4% of those on omalizumab and 36.3% of those on placebo for an odds ratio of 0.12 (95% CI, 0.02-0.64).

“And they only used the biologic for 4 months,” Oppenheimer said. “Maybe the answer is we don’t have to use it all year long. We can use it at times of exacerbation.”

Omalizumab also may be able to prevent asthma in toddlers at high risk, including aeroallergen sensitization via allergen-specific antibody production and viral lower respiratory tract infections, Oppenheimer said.

By blocking circulating IgE and IgE-mediated responses, he said, early treatment may prevent asthma development in children who do not have it yet or reduce its severity in those children who develop it.

The NIH is now funding a study that will observe children aged 2 to 3 years with wheeze but not asthma treated with omalizumab for 2 years and observed for a total of 4 years to see if it decreases asthma severity.

“The most interesting part of this study is, can we actually prevent asthma from taking off, from escalating, by treating earlier?” Oppenheimer said.

Next steps

Oppenheimer said that omalizumab was first approved for asthma treatment in 2003 and that biologics and other technologies alike have broken new ground in the decades since then.

Depemokimab, a new anti-IL5 therapy that is now being studied, appears to work for 6 months, Oppenheimer said. Oppenheimer called it a “biobetter,” which takes a mechanism and improves upon the compound.

Patients in one depemokimab study experienced a greater than 48% reduction in blood eosinophil count just 24 hours after receiving their first dose, with increasing doses leading to maintained suppression.

“Maybe we’ll be thinking about using biologics earlier in disease severity, and maybe we can even develop a biobetter that would be once a year,” Oppenheimer said. “Wouldn’t that be game-changing for patients?”

Oppenheimer encouraged the audience to consider what may come in the next 20 years. Goals include better defining who is more likely to respond to specific agents, eliminating misuse and achieving better precision in both phenotype and genotype.

Seasonal use of biologics also may increase, he continued, along with more patients experiencing remission and possibly prevention.

“It’s a biologic world,” he said, “and it’s only going to grow.”