Through an adaptive research trial, doctors and patients from 30 U.S. study locations are working together to study if five new medications can help patients with severe asthma by altering the underlying biology of this airway disease.
As Erin Routh prepares to walk in winter weather, she does more than put on a jacket, hat, and gloves. The 46-year-old North Carolina resident often “pretreats” her asthma to prepare for her biggest trigger: changing temperatures. Otherwise, her chest tightens. Her airways constrict. It becomes hard to breathe.
Routh’s winter routine may include using two different types of asthma inhalers before she walks outside, keeping medications and a rescue inhaler handy, and covering her mouth and nose to help her body regulate temperature. In the best-case scenario, Routh experiences mild discomfort as cold air seeps into her airways and lungs. Oftentimes, she must wait a few minutes before medications, if needed, take effect. In the worst-case scenario, which, fortunately, hasn’t happened recently, it could mean rushing to the emergency room for treatment.
Routh, who was diagnosed with asthma when she was 6-months old, is one of about 25 million Americans living with asthma. She is also one of 75,000 to 2,500,000 people, 3-10% of all asthma patients, with a severe case. This frequently causes symptoms that are difficult to control. To help researchers identify ways to help patients like herself, she is participating in an asthma study led by researchers across the U.S., which is funded by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.
The adaptive research trial, the Precision Interventions for Severe and/or Exacerbation-Prone Asthma Network (PrecISE), started in 2019 and is enrolling up to 600 teenagers and adults at 30 locations throughout 2023 to test how two novel and three existing treatments used for other inflammatory conditions may help treat severe or uncontrolled asthma.
Personalizing asthma research
“Many different types of people can be classified as having severe asthma,” explained Patricia Noel, Ph.D., a program director in NHLBI’s Division of Lung Diseases. “This may be because there are different biological mechanisms in their body that are actually causing their severe asthma.” A unique aspect of PrecISE is matching patients who fit into a variety of severe asthma subtypes with medications that may alter the underlying biology of their airway disease. Upon enrolling in the study, participants engage in different tests to characterize these pathways – which helps the researchers match participants with treatments, while also testing their predictions about which treatments may work best.
“We’re testing everything from injectable medications to dietary supplements,” Noel explained. “It’s really important for these patients, who don’t respond well to treatment or for whom asthma has had such a huge impact on their life, that we continue to push forward and find novel treatments that can be tested efficiently,” she said.
The medications studied in PrecISE include an injectable medication that alters inflammatory pathways in arthritis and cardiovascular disease; a dietary supplement that changes how the body breaks down and uses energy, which is used to support brain and cardiovascular health; an oral medication used to treat certain types of cancer; and two other oral medications developed to treat other respiratory conditions.
“We don’t understand all of the biology of severe asthma,” said Noel. That’s where the adaptive nature of the trial comes in. Researchers can quickly evaluate if the predictions they are making about “matched” treatments improve asthma symptoms in patients. They are also evaluating if the same treatments could help people who don’t share the same underlying asthma biology.
Throughout each intervention, which lasts for four months, researchers will study potential changes in airway and lung function among patients. Patients will share asthma diaries and complete asthma self-assessments. This includes answering questions about how well they slept each night, how often they used medications, symptoms they experienced, like wheezing or having an asthma attack, and if they needed emergency treatment.
If a treatment proves effective, it could advance to larger trials. The goal of this Phase 2 study is to first evaluate treatment efficacy with hundreds of patients. Then, pending results, a medication could proceed to a Phase 3 trial, where it would be studied for its ability to treat severe asthma within a larger population. Following success in those trials, paired with rigorous safety reviews, a treatment could then be considered for approval by the Food and Drug Administration (FDA) for its use in treating severe asthma.
But, for now, it’s too early to predict which treatments, if any, may have this effect.
Studying “outside-in” inflammation
One treatment approach that researchers are studying in PreCISE is the ability to control inflammation that may start outside of the lungs, referred to as “outside-in” inflammation.
To assesses indicators of this type of inflammation, researchers analyze levels of interleukin-6 (IL-6) from blood samples they receive from patients.
“The IL-6 story began probably close to 10 years ago now,” explained Sally Wenzel, M.D., a PrecISE researcher and the director of the Asthma and Environmental Lung Health Institute at the University of Pittsburgh.
Patients with asthma who had higher levels of IL-6 often had worse symptoms. This includes lower lung function, more asthma exacerbations, more asthma symptoms, and a slightly higher need for anti-inflammatory medications, like steroids. In some cases, IL-6 levels proportionately increased with metabolic conditions, like obesity or having a higher body mass index.
Systemic inflammation, the kind associated with obesity, diabetes, and cardiovascular disease, may create a “second hit” of inflammation and make asthma symptoms worse, Wenzel explained. “You have some underlying problem in the lungs that perhaps starts the process but is relatively mild,” she said. “Then you put the systemic inflammation on top of it as your second hit and then you develop more severe disease. So, blocking IL-6 seemed to be a natural target.”
Clazakizumab, a monoclonal antibody, inhibits IL-6 and is currently used to help patients with cardiovascular disease and arthritis. Wenzel and the PrecISE researchers are seeing if the treatment may also help patients with severe asthma. “Biologically, we know it does the right thing,” Wenzel said. However, like other interventions, they will see who responds, if at all, to the treatment.
For example, about one-third of patients with severe asthma have elevated IL-6 levels. However, not all asthma patients have cardiovascular disease risk factors, like obesity or diabetes, that could further exacerbate airway inflammation.
There is also room built into the trial to enable researchers to expand on early observations, such as enrolling more patients with slightly higher or lower elevated IL-6 levels. This would help if one group shows a more beneficial response to the treatment.
“The focus is bringing the right treatment to the right patient,” Wenzel explained.
Making a childhood wish come true
Routh, the North Carolina study participant, has participated in clinical research studies at Wake Forest University over the past 10-12 years to see if she can find that right treatment.
She fits into a “type 2 inflammation” subtype of severe asthma, which is characteristic of experiencing a greater number of asthma attacks and characteristic of other factors, like having increased levels of eosinophils, a pro-inflammatory white blood cell. Wenzel explains that several approved drugs targeting those pathways can be “game changers” for some patients.
After participating in a two-year study to test the biologic Tezspire, Routh had that experience.
“There were times I forgot I had asthma,” she said.
While she was in that study that meant no longer keeping an inhaler in her pocketbook, not worrying about pretreating her airways before stepping outside, and not having to think about avoiding other triggers, like being around cats or dogs while visiting friends or family members.
“When I had those realizations, it was wonderful,” Routh said. She plans to take the biologic, which was recently approved by the FDA, again in the future.
Routh’s journey to find another asthma treatment started at the height of severe exacerbations she experienced while she was pregnant in 2008. “It was just the worst it had ever been,” she said. She took a daily dose of prednisone, an oral steroid, but the medication required her to take short-term disability leave during her pregnancy.
After her daughter was born, she started looking for an oral steroid replacement.
This is what led her to asthma studies, like PrecISE.
In 2019, she enrolled in the treatment arm for clazakizumab, the IL-6 inhibitor. At the time, she wasn’t sure if she was receiving the treatment or a placebo.
A placebo is a medical “duplicate” that looks just like treatment, but it contains no medicine and serves as a control. The goal is to enable researchers to compare an equal number of patients receiving treatment to those receiving none but who share similar characteristics. To preserve the integrity of the study, the trial is double blinded – meaning neither patients nor researchers know who is receiving the treatment until the intervention ends.
“For things like this to be created and to actually work for me, it’s magical,” she said, noting her previous experience with asthma trials, including Tezspire, and her willingness to try other biologics through future studies if she’s a good match.
Like the researchers, she’s looking for a treatment to control severe asthma instead of alleviating its symptoms. And she hopes that through ongoing research, scientists can identify the right treatment strategies to help patients like herself.
“When I was growing up, I had so many health issues,” she said. “I always used to think, wouldn’t it be nice if people could have wishes granted.”
“It sounds so simple and kind of hokey,” she added. “But I would always think, my first wish would be to not have asthma. Not to have to struggle so much.”
Like Routh, the researchers hope that these types of trials can help make those types of wishes come true.
To learn more about asthma, visit https://www.nhlbi.nih.gov/LMBBasthma.
To learn more about PrecISE, visit https://preciseasthma.org/preciseweb/.