Pulmonology

In a real-world study of asthma patients, treatment with biologics following an exacerbation was associated with better health care utilization outcomes.

The data fill a gap, according to Sushan Gupta, MD, who presented the results at the annual meeting of the American College of Chest Physicians. “There’s some ample real-world data that shows that biologics reduce the incidence of asthma exacerbation, but the data regarding what happens after an exacerbation is still lacking, especially real-world data,” said Dr. Gupta, who is a resident at Carle Foundation Hospital in Champaign, Ill.

The findings were encouraging. “Patients with severe asthma on biologics fare well even after an exacerbation event, which includes a reduced incidence of hospitalization, ICU admission, and need for mechanical ventilation. We did not have any patient in the biologic group that required intubation, so that is pretty significant as compared to other patients who did not receive biologics,” said Dr. Gupta.

The results weren’t surprising, but underscore the benefits of biologics, according to Brittany Duchene, MD, who moderated the session where the results were presented. “I think it reinforced that they’re really good drugs,” said Dr. Duchene, who is a pulmonary critical care physician at Northeastern Vermont Regional Hospital, St. Johnsbury.

Although the study was retrospective, it suggests that the threshold for initiating biologics could potentially be lowered for patients with uncontrolled asthma despite adequate use of inhalers, according to Dr. Gupta. “Should that threshold be lower, and would that improve the overall morbidity and eventually the health care cost of utilization? Our study does not prove any of those data, but moving forward that data will also come out.”

Dr. Duchene noted that the accumulating scientific and clinical data for biologics is “really, really strong.” She also speculated that biologics could be used increasingly in the acute setting, which she admitted is a controversial topic. “I think there’s going to be a lot more push to early initiation, and you can see from the [new] study that it decreased a lot of hospitalizations.”

Dr. Gupta emphasized the need for prospective studies, and Dr. Duchene agreed that any such change would need to be patient centric, considering the diversity of available biologics. “It depends what their true issue is. The broader the biologic [mechanism of action], probably the more success you’ll have. I’ve found there’s not a pure allergic or a pure eosinophilic asthma patient. They’re usually more a combination.”

Some key questions remain about biologics treatment, especially in the long term. These include when a patient should be switched from one biologic to another, and whether biologic treatment should be continued over the patient’s lifetime and potential long-term side effects. “I think that data is still evolving and will come to us with time,” said Dr. Gupta.

The researchers analyzed retrospective data from 316 asthma patients treated with biologics and 9,645 treated with nonbiologic therapy between February 2018 and February 2023 at a tertiary care teaching hospital in the Midwest. There was a higher proportion of females in the biologics (69.7%) and nonbiologics groups (63.8%, P = .032), but there was no significant difference in the proportion of Whites in the biologics and nonbiologics groups (78.2% vs. 74.3%, P = .103).

The lack of a difference in racial groups was a surprise, according to Dr. Duchene, especially since other studies have noted disparities in biologic therapy among asthma patients.

Among the biologics group, 0.9% were hospitalized during the study period, compared with 6.5% of the nonbiologics group (P = .00006). They also had fewer ICU visits (0.3% vs. 1.8%; P = .04).

Dr. Gupta’s team attempted to subdivide the data by individual biologic, but there was no statistical significance in outcomes between biologics, perhaps because of the relatively small sample size.

Dr. Gupta noted that his group’s results are generally similar to other studies, including a U.S. study that found a decrease in exacerbation rates after staring or switching biologics and a slightly higher prevalence of biologics use among White patients (77% of biologic users versus 71% of nonbiologics users). A study in southwestern England found fewer ED visits and hospitalizations among patients on biologics.

Dr. Gupta and Dr. Duchene have no relevant financial disclosures.
 

In a real-world study of asthma patients, treatment with biologics following an exacerbation was associated with better health care utilization outcomes.

The data fill a gap, according to Sushan Gupta, MD, who presented the results at the annual meeting of the American College of Chest Physicians. “There’s some ample real-world data that shows that biologics reduce the incidence of asthma exacerbation, but the data regarding what happens after an exacerbation is still lacking, especially real-world data,” said Dr. Gupta, who is a resident at Carle Foundation Hospital in Champaign, Ill.

The findings were encouraging. “Patients with severe asthma on biologics fare well even after an exacerbation event, which includes a reduced incidence of hospitalization, ICU admission, and need for mechanical ventilation. We did not have any patient in the biologic group that required intubation, so that is pretty significant as compared to other patients who did not receive biologics,” said Dr. Gupta.

The results weren’t surprising, but underscore the benefits of biologics, according to Brittany Duchene, MD, who moderated the session where the results were presented. “I think it reinforced that they’re really good drugs,” said Dr. Duchene, who is a pulmonary critical care physician at Northeastern Vermont Regional Hospital, St. Johnsbury.

Although the study was retrospective, it suggests that the threshold for initiating biologics could potentially be lowered for patients with uncontrolled asthma despite adequate use of inhalers, according to Dr. Gupta. “Should that threshold be lower, and would that improve the overall morbidity and eventually the health care cost of utilization? Our study does not prove any of those data, but moving forward that data will also come out.”

Dr. Duchene noted that the accumulating scientific and clinical data for biologics is “really, really strong.” She also speculated that biologics could be used increasingly in the acute setting, which she admitted is a controversial topic. “I think there’s going to be a lot more push to early initiation, and you can see from the [new] study that it decreased a lot of hospitalizations.”

Dr. Gupta emphasized the need for prospective studies, and Dr. Duchene agreed that any such change would need to be patient centric, considering the diversity of available biologics. “It depends what their true issue is. The broader the biologic [mechanism of action], probably the more success you’ll have. I’ve found there’s not a pure allergic or a pure eosinophilic asthma patient. They’re usually more a combination.”

Some key questions remain about biologics treatment, especially in the long term. These include when a patient should be switched from one biologic to another, and whether biologic treatment should be continued over the patient’s lifetime and potential long-term side effects. “I think that data is still evolving and will come to us with time,” said Dr. Gupta.

The researchers analyzed retrospective data from 316 asthma patients treated with biologics and 9,645 treated with nonbiologic therapy between February 2018 and February 2023 at a tertiary care teaching hospital in the Midwest. There was a higher proportion of females in the biologics (69.7%) and nonbiologics groups (63.8%, P = .032), but there was no significant difference in the proportion of Whites in the biologics and nonbiologics groups (78.2% vs. 74.3%, P = .103).

The lack of a difference in racial groups was a surprise, according to Dr. Duchene, especially since other studies have noted disparities in biologic therapy among asthma patients.

Among the biologics group, 0.9% were hospitalized during the study period, compared with 6.5% of the nonbiologics group (P = .00006). They also had fewer ICU visits (0.3% vs. 1.8%; P = .04).

Dr. Gupta’s team attempted to subdivide the data by individual biologic, but there was no statistical significance in outcomes between biologics, perhaps because of the relatively small sample size.

Dr. Gupta noted that his group’s results are generally similar to other studies, including a U.S. study that found a decrease in exacerbation rates after staring or switching biologics and a slightly higher prevalence of biologics use among White patients (77% of biologic users versus 71% of nonbiologics users). A study in southwestern England found fewer ED visits and hospitalizations among patients on biologics.

Dr. Gupta and Dr. Duchene have no relevant financial disclosures.
 

In a real-world study of asthma patients, treatment with biologics following an exacerbation was associated with better health care utilization outcomes.

The data fill a gap, according to Sushan Gupta, MD, who presented the results at the annual meeting of the American College of Chest Physicians. “There’s some ample real-world data that shows that biologics reduce the incidence of asthma exacerbation, but the data regarding what happens after an exacerbation is still lacking, especially real-world data,” said Dr. Gupta, who is a resident at Carle Foundation Hospital in Champaign, Ill.

The findings were encouraging. “Patients with severe asthma on biologics fare well even after an exacerbation event, which includes a reduced incidence of hospitalization, ICU admission, and need for mechanical ventilation. We did not have any patient in the biologic group that required intubation, so that is pretty significant as compared to other patients who did not receive biologics,” said Dr. Gupta.

The results weren’t surprising, but underscore the benefits of biologics, according to Brittany Duchene, MD, who moderated the session where the results were presented. “I think it reinforced that they’re really good drugs,” said Dr. Duchene, who is a pulmonary critical care physician at Northeastern Vermont Regional Hospital, St. Johnsbury.

Although the study was retrospective, it suggests that the threshold for initiating biologics could potentially be lowered for patients with uncontrolled asthma despite adequate use of inhalers, according to Dr. Gupta. “Should that threshold be lower, and would that improve the overall morbidity and eventually the health care cost of utilization? Our study does not prove any of those data, but moving forward that data will also come out.”

Dr. Duchene noted that the accumulating scientific and clinical data for biologics is “really, really strong.” She also speculated that biologics could be used increasingly in the acute setting, which she admitted is a controversial topic. “I think there’s going to be a lot more push to early initiation, and you can see from the [new] study that it decreased a lot of hospitalizations.”

Dr. Gupta emphasized the need for prospective studies, and Dr. Duchene agreed that any such change would need to be patient centric, considering the diversity of available biologics. “It depends what their true issue is. The broader the biologic [mechanism of action], probably the more success you’ll have. I’ve found there’s not a pure allergic or a pure eosinophilic asthma patient. They’re usually more a combination.”

Some key questions remain about biologics treatment, especially in the long term. These include when a patient should be switched from one biologic to another, and whether biologic treatment should be continued over the patient’s lifetime and potential long-term side effects. “I think that data is still evolving and will come to us with time,” said Dr. Gupta.

The researchers analyzed retrospective data from 316 asthma patients treated with biologics and 9,645 treated with nonbiologic therapy between February 2018 and February 2023 at a tertiary care teaching hospital in the Midwest. There was a higher proportion of females in the biologics (69.7%) and nonbiologics groups (63.8%, P = .032), but there was no significant difference in the proportion of Whites in the biologics and nonbiologics groups (78.2% vs. 74.3%, P = .103).

The lack of a difference in racial groups was a surprise, according to Dr. Duchene, especially since other studies have noted disparities in biologic therapy among asthma patients.

Among the biologics group, 0.9% were hospitalized during the study period, compared with 6.5% of the nonbiologics group (P = .00006). They also had fewer ICU visits (0.3% vs. 1.8%; P = .04).

Dr. Gupta’s team attempted to subdivide the data by individual biologic, but there was no statistical significance in outcomes between biologics, perhaps because of the relatively small sample size.

Dr. Gupta noted that his group’s results are generally similar to other studies, including a U.S. study that found a decrease in exacerbation rates after staring or switching biologics and a slightly higher prevalence of biologics use among White patients (77% of biologic users versus 71% of nonbiologics users). A study in southwestern England found fewer ED visits and hospitalizations among patients on biologics.

Dr. Gupta and Dr. Duchene have no relevant financial disclosures.
 

HONOLULU – There’s new evidence to support a practice that many pulmonologists have been doing empirically anyway: namely, reducing the dose of the antifibrotic medication nintedanib (Ofev) for patients with idiopathic pulmonary fibrosis (IPF) who can’t tolerate the full 150-mg twice-daily dose.

An analysis of data from a large administrative claims database showed that there were no significant differences in either all-cause mortality or hospitalization rates between patients with IPF treated at the full 150-mg twice-daily dose and those treated with a reduced twice-daily dose of 100 mg nintedanib.

Although the results need to be confirmed by additional prospective and registry studies, they suggest that patients with IPF can still fare just as well with a reduced-dose nintedanib regimen, ideally with fewer gastrointestinal side effects such as diarrhea, reported Andrew Limper, MD, of the Mayo Clinic in Rochester, Minn.

“At least on this preliminary data you could ... rest assured,” Dr. Limper told his colleagues in an oral abstract session at the American College of Chest Physicians (CHEST) 2023 annual meeting.

“This is not definitive proof, I’m not making more out of this than it is, but we all put people on 100 mg twice daily because their guts don’t tolerate it; they live in the bathroom and they don’t want to live that way,” Dr. Limper said.
 

Hard to take

Nintedanib is approved in the United States for the treatment of IPF, chronic fibrosing interstitial lung diseases (ILD) with a progressive phenotype, and systemic sclerosis-associated ILD. For IPF, the standard dose established in randomized clinical trials is 150 mg twice daily.

However, nintedanib is associated with a number of side effects, including hepatic and other gastrointestinal toxicities, arterial thromboembolic events, and proteinuria within the nephrotic range. As a result, clinicians often reduce the dose to 100 mg twice daily, but there is a lack of data to indicate whether it’s safe to do so or if efficacy will be compromised.

To see whether dose reductions might result in poorer outcomes for patients with IPF, Dr. Limper and colleagues analyzed data from the OptumLabs Data Warehouse, a large administrative claims database, to compare outcomes for patients treated with IPF at either the 150-mg or 100-mg twice-daily doses.

They used propensity-score matching to account for differences among individuals according to age, sex, race/ethnicity, residence, insurance type, additional medication use, oxygen use, smoking status, health care use, and comorbidities. The final cohort included 346 patients in each dosing group.

There was no difference between the dosing groups for the primary outcome of all-cause mortality at 18 months, with a nonsignificant hazard ratio of 0.65 (P = .313), and no significant difference over 24 months in risk of hospitalization, with a hazard ratio of 0.98 (P = .899).

“This is not randomized controlled data; I doubt that [nintedanib maker Boehringer Ingelheim] is ever going to do a 150 vs. 100 milligram head-to-head trial, but it does give us some ground to start to look at this,” Dr. Limper said.
 

Not so sure

Session comoderator Misbah Baqir, MBBS, also from the Mayo Clinic, told this news organization that she would need to see more data from prospective studies using endpoints other than mortality before she could be convinced that nintedanib dose reductions do not adversely affect efficacy. She was not involved in the study.

“I feel that the endpoint should be different, either it should be forced vital capacity change, quality of life, or something else. The problem with a database study is that you don’t have everything in it. You have to play with what you have, and you don’t have forced vital capacity. You have to go into the charts to get it,” she said.

It would be more helpful to objectively compare, for example, diarrhea episodes or other adverse events to see whether they were significantly reduced with the 100-mg dose, she added.

In an interview, Dr. Limper said that he and his colleagues plan to gather additional observational data including the newly available Medicare fee-for-service data set, registry data, and other sources.

“If we get all of that, and it really still looks compelling – and that’s an if – then I think that would be the foothold to go back to the manufacturer and say, ‘Hey, maybe you ought to think about doing a prospective trial to prove it with lung function and other endpoints such as 6-minute walks,’ ” he said.

The study was supported by a grant from Three Lakes Foundation. Dr. Limper and Dr. Baqir have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

HONOLULU – There’s new evidence to support a practice that many pulmonologists have been doing empirically anyway: namely, reducing the dose of the antifibrotic medication nintedanib (Ofev) for patients with idiopathic pulmonary fibrosis (IPF) who can’t tolerate the full 150-mg twice-daily dose.

An analysis of data from a large administrative claims database showed that there were no significant differences in either all-cause mortality or hospitalization rates between patients with IPF treated at the full 150-mg twice-daily dose and those treated with a reduced twice-daily dose of 100 mg nintedanib.

Although the results need to be confirmed by additional prospective and registry studies, they suggest that patients with IPF can still fare just as well with a reduced-dose nintedanib regimen, ideally with fewer gastrointestinal side effects such as diarrhea, reported Andrew Limper, MD, of the Mayo Clinic in Rochester, Minn.

“At least on this preliminary data you could ... rest assured,” Dr. Limper told his colleagues in an oral abstract session at the American College of Chest Physicians (CHEST) 2023 annual meeting.

“This is not definitive proof, I’m not making more out of this than it is, but we all put people on 100 mg twice daily because their guts don’t tolerate it; they live in the bathroom and they don’t want to live that way,” Dr. Limper said.
 

Hard to take

Nintedanib is approved in the United States for the treatment of IPF, chronic fibrosing interstitial lung diseases (ILD) with a progressive phenotype, and systemic sclerosis-associated ILD. For IPF, the standard dose established in randomized clinical trials is 150 mg twice daily.

However, nintedanib is associated with a number of side effects, including hepatic and other gastrointestinal toxicities, arterial thromboembolic events, and proteinuria within the nephrotic range. As a result, clinicians often reduce the dose to 100 mg twice daily, but there is a lack of data to indicate whether it’s safe to do so or if efficacy will be compromised.

To see whether dose reductions might result in poorer outcomes for patients with IPF, Dr. Limper and colleagues analyzed data from the OptumLabs Data Warehouse, a large administrative claims database, to compare outcomes for patients treated with IPF at either the 150-mg or 100-mg twice-daily doses.

They used propensity-score matching to account for differences among individuals according to age, sex, race/ethnicity, residence, insurance type, additional medication use, oxygen use, smoking status, health care use, and comorbidities. The final cohort included 346 patients in each dosing group.

There was no difference between the dosing groups for the primary outcome of all-cause mortality at 18 months, with a nonsignificant hazard ratio of 0.65 (P = .313), and no significant difference over 24 months in risk of hospitalization, with a hazard ratio of 0.98 (P = .899).

“This is not randomized controlled data; I doubt that [nintedanib maker Boehringer Ingelheim] is ever going to do a 150 vs. 100 milligram head-to-head trial, but it does give us some ground to start to look at this,” Dr. Limper said.
 

Not so sure

Session comoderator Misbah Baqir, MBBS, also from the Mayo Clinic, told this news organization that she would need to see more data from prospective studies using endpoints other than mortality before she could be convinced that nintedanib dose reductions do not adversely affect efficacy. She was not involved in the study.

“I feel that the endpoint should be different, either it should be forced vital capacity change, quality of life, or something else. The problem with a database study is that you don’t have everything in it. You have to play with what you have, and you don’t have forced vital capacity. You have to go into the charts to get it,” she said.

It would be more helpful to objectively compare, for example, diarrhea episodes or other adverse events to see whether they were significantly reduced with the 100-mg dose, she added.

In an interview, Dr. Limper said that he and his colleagues plan to gather additional observational data including the newly available Medicare fee-for-service data set, registry data, and other sources.

“If we get all of that, and it really still looks compelling – and that’s an if – then I think that would be the foothold to go back to the manufacturer and say, ‘Hey, maybe you ought to think about doing a prospective trial to prove it with lung function and other endpoints such as 6-minute walks,’ ” he said.

The study was supported by a grant from Three Lakes Foundation. Dr. Limper and Dr. Baqir have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

HONOLULU – There’s new evidence to support a practice that many pulmonologists have been doing empirically anyway: namely, reducing the dose of the antifibrotic medication nintedanib (Ofev) for patients with idiopathic pulmonary fibrosis (IPF) who can’t tolerate the full 150-mg twice-daily dose.

An analysis of data from a large administrative claims database showed that there were no significant differences in either all-cause mortality or hospitalization rates between patients with IPF treated at the full 150-mg twice-daily dose and those treated with a reduced twice-daily dose of 100 mg nintedanib.

Although the results need to be confirmed by additional prospective and registry studies, they suggest that patients with IPF can still fare just as well with a reduced-dose nintedanib regimen, ideally with fewer gastrointestinal side effects such as diarrhea, reported Andrew Limper, MD, of the Mayo Clinic in Rochester, Minn.

“At least on this preliminary data you could ... rest assured,” Dr. Limper told his colleagues in an oral abstract session at the American College of Chest Physicians (CHEST) 2023 annual meeting.

“This is not definitive proof, I’m not making more out of this than it is, but we all put people on 100 mg twice daily because their guts don’t tolerate it; they live in the bathroom and they don’t want to live that way,” Dr. Limper said.
 

Hard to take

Nintedanib is approved in the United States for the treatment of IPF, chronic fibrosing interstitial lung diseases (ILD) with a progressive phenotype, and systemic sclerosis-associated ILD. For IPF, the standard dose established in randomized clinical trials is 150 mg twice daily.

However, nintedanib is associated with a number of side effects, including hepatic and other gastrointestinal toxicities, arterial thromboembolic events, and proteinuria within the nephrotic range. As a result, clinicians often reduce the dose to 100 mg twice daily, but there is a lack of data to indicate whether it’s safe to do so or if efficacy will be compromised.

To see whether dose reductions might result in poorer outcomes for patients with IPF, Dr. Limper and colleagues analyzed data from the OptumLabs Data Warehouse, a large administrative claims database, to compare outcomes for patients treated with IPF at either the 150-mg or 100-mg twice-daily doses.

They used propensity-score matching to account for differences among individuals according to age, sex, race/ethnicity, residence, insurance type, additional medication use, oxygen use, smoking status, health care use, and comorbidities. The final cohort included 346 patients in each dosing group.

There was no difference between the dosing groups for the primary outcome of all-cause mortality at 18 months, with a nonsignificant hazard ratio of 0.65 (P = .313), and no significant difference over 24 months in risk of hospitalization, with a hazard ratio of 0.98 (P = .899).

“This is not randomized controlled data; I doubt that [nintedanib maker Boehringer Ingelheim] is ever going to do a 150 vs. 100 milligram head-to-head trial, but it does give us some ground to start to look at this,” Dr. Limper said.
 

Not so sure

Session comoderator Misbah Baqir, MBBS, also from the Mayo Clinic, told this news organization that she would need to see more data from prospective studies using endpoints other than mortality before she could be convinced that nintedanib dose reductions do not adversely affect efficacy. She was not involved in the study.

“I feel that the endpoint should be different, either it should be forced vital capacity change, quality of life, or something else. The problem with a database study is that you don’t have everything in it. You have to play with what you have, and you don’t have forced vital capacity. You have to go into the charts to get it,” she said.

It would be more helpful to objectively compare, for example, diarrhea episodes or other adverse events to see whether they were significantly reduced with the 100-mg dose, she added.

In an interview, Dr. Limper said that he and his colleagues plan to gather additional observational data including the newly available Medicare fee-for-service data set, registry data, and other sources.

“If we get all of that, and it really still looks compelling – and that’s an if – then I think that would be the foothold to go back to the manufacturer and say, ‘Hey, maybe you ought to think about doing a prospective trial to prove it with lung function and other endpoints such as 6-minute walks,’ ” he said.

The study was supported by a grant from Three Lakes Foundation. Dr. Limper and Dr. Baqir have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Nirmatrelvir-ritonavir (Paxlovid) is associated with a reduced risk for death or hospitalization in the most extremely vulnerable patients with COVID-19, new research suggests.

In a cohort study from British Columbia that included nearly 7,000 patients with COVID-19, nirmatrelvir-ritonavir was associated with a 2.5% reduction in risk for death or emergency hospitalization in clinically extremely vulnerable (CEV) patients who were severely immunocompromised. No significant benefit was observed in patients who were not immunocompromised.

“This finding could help substantially limit unnecessary use of nirmatrelvir and ritonavir in older, otherwise healthy individuals,” lead author Colin R. Dormuth, ScD, associate professor of anesthesiology, pharmacology, and therapeutics at the University of British Columbia, Vancouver, told this news organization. “Another finding that was surprising and might help place the role of nirmatrelvir and ritonavir in context is that even in severely immunocompromised individuals who did not take [the drug], the risk of death or hospitalization with COVID-19 was less than 4% in our study population.”

The study was published online in JAMA Network Open.
 

Who benefits?

The investigators analyzed medical records for 6,866 patients in British Columbia (median age, 70 years; 57% women) who presented between Feb. 1, 2022, and Feb. 3, 2023. Eligible patients belonged to one of four higher-risk groups who received priority for COVID-19 vaccination.

Two groups included CEV patients who were severely (CEV1) or moderately (CEV2) immunocompromised. The CEV3 group was not immunocompromised but had medical conditions associated with a high risk for complications from COVID-19. A fourth expanded eligibility (EXEL) group included higher-risk patients who were not in one of the other groups, such as unvaccinated patients older than age 70 years.

The investigators matched treated patients to untreated patients in the same vulnerability group according to age, sex, and month of infection. The primary outcome was death from any cause or emergency hospitalization with COVID-19 within 28 days.

Treatment with nirmatrelvir-ritonavir was associated with statistically significant relative reductions in the primary outcome, compared with no treatment, for patients in the CEV1 (risk difference, −2.5%) and CEV2 (RD, −1.7%) groups. In the CEV3 group, the RD of −1.3% was not statistically significant. In the EXEL group, treatment was associated with a higher risk for the primary outcome (RD, 1.0%), but the result was not statistically significant.

The results were “robust across sex and older vs. younger age,” the authors note. “No reduction in the primary outcome was observed in lower-risk individuals, including those aged 70 years or older without serious comorbidities.”

The combination of nirmatrelvir-ritonavir was approved for use in Canada based on interim efficacy and safety data from the Evaluation of Inhibition for COVID-19 in High-Risk Patients (EPIC-HR) trial, said Dr. Dormuth.

British Columbia’s eligibility criteria for nirmatrelvir-ritonavir coverage differ substantially from the criteria for participants in the EPIC-HR trial, he noted. Those patients were unvaccinated, had no natural immunity from a previous COVID-19 infection, and were infected with COVID-19 variants that were different from those now circulating. The current study was prompted by the need to look at a broader population of individuals in British Columbia with varying risks of complications from COVID-19 infection.

Before the study, a common view was that patients aged 70 and older would benefit from the drug, said Dr. Dormuth. “Our study, which accounted for medical conditions related to an individual’s vulnerability to complications, showed that older age on its own was not a reason to use nirmatrelvir and ritonavir once relevant medical conditions were taken into consideration.”

The researchers are working on a study to identify with greater specificity which comorbid conditions are most associated with nirmatrelvir-ritonavir effectiveness, he added. “It could be that a relatively small number of conditions can be used to identify most individuals who would benefit from the drug.”
 

‘Signal toward benefit’

Commenting on the findings for this news organization, Abhijit Duggal, MD, vice chair of critical care at the Cleveland Clinic, who was not involved in this study, said, “I’m always very wary when we look at observational data and we start saying the effectiveness is not really as high as was seen in other studies. We are seeing an effect with all these studies that seems to be in the right direction.

“Having said that,” he added, “is the effect going to be potentially more in patients at higher risk? Absolutely. I think these postmarket studies are really showing that after vaccination, if someone does get infected, this is a secondary option available to us that can prevent progression of the disease, which would likely be more severe in immunocompromised patients.”

Dr. Duggal was a coinvestigator on a recent study of more than 68,000 patients that showed that nirmatrelvir-ritonavir or molnupiravir was associated with reductions in mortality and hospitalization in nonhospitalized patients infected with the Omicron variant, regardless of age, race and ethnicity, virus strain, vaccination status, previous infection status, or coexisting conditions.

“In all groups, there was a signal toward benefit,” said Dr. Duggal. “These studies tell us that these drugs do remain valid options. But their use needs to be discussed on a case-by-case basis with patients we feel are deteriorating or at a higher risk because of underlying disease processes.”

The study was supported by funding from the British Columbia Ministry of Health. Dr. Dormuth and Dr. Duggal report no relevant financial relationships.

A version of this article appeared on Medscape.com.

Nirmatrelvir-ritonavir (Paxlovid) is associated with a reduced risk for death or hospitalization in the most extremely vulnerable patients with COVID-19, new research suggests.

In a cohort study from British Columbia that included nearly 7,000 patients with COVID-19, nirmatrelvir-ritonavir was associated with a 2.5% reduction in risk for death or emergency hospitalization in clinically extremely vulnerable (CEV) patients who were severely immunocompromised. No significant benefit was observed in patients who were not immunocompromised.

“This finding could help substantially limit unnecessary use of nirmatrelvir and ritonavir in older, otherwise healthy individuals,” lead author Colin R. Dormuth, ScD, associate professor of anesthesiology, pharmacology, and therapeutics at the University of British Columbia, Vancouver, told this news organization. “Another finding that was surprising and might help place the role of nirmatrelvir and ritonavir in context is that even in severely immunocompromised individuals who did not take [the drug], the risk of death or hospitalization with COVID-19 was less than 4% in our study population.”

The study was published online in JAMA Network Open.
 

Who benefits?

The investigators analyzed medical records for 6,866 patients in British Columbia (median age, 70 years; 57% women) who presented between Feb. 1, 2022, and Feb. 3, 2023. Eligible patients belonged to one of four higher-risk groups who received priority for COVID-19 vaccination.

Two groups included CEV patients who were severely (CEV1) or moderately (CEV2) immunocompromised. The CEV3 group was not immunocompromised but had medical conditions associated with a high risk for complications from COVID-19. A fourth expanded eligibility (EXEL) group included higher-risk patients who were not in one of the other groups, such as unvaccinated patients older than age 70 years.

The investigators matched treated patients to untreated patients in the same vulnerability group according to age, sex, and month of infection. The primary outcome was death from any cause or emergency hospitalization with COVID-19 within 28 days.

Treatment with nirmatrelvir-ritonavir was associated with statistically significant relative reductions in the primary outcome, compared with no treatment, for patients in the CEV1 (risk difference, −2.5%) and CEV2 (RD, −1.7%) groups. In the CEV3 group, the RD of −1.3% was not statistically significant. In the EXEL group, treatment was associated with a higher risk for the primary outcome (RD, 1.0%), but the result was not statistically significant.

The results were “robust across sex and older vs. younger age,” the authors note. “No reduction in the primary outcome was observed in lower-risk individuals, including those aged 70 years or older without serious comorbidities.”

The combination of nirmatrelvir-ritonavir was approved for use in Canada based on interim efficacy and safety data from the Evaluation of Inhibition for COVID-19 in High-Risk Patients (EPIC-HR) trial, said Dr. Dormuth.

British Columbia’s eligibility criteria for nirmatrelvir-ritonavir coverage differ substantially from the criteria for participants in the EPIC-HR trial, he noted. Those patients were unvaccinated, had no natural immunity from a previous COVID-19 infection, and were infected with COVID-19 variants that were different from those now circulating. The current study was prompted by the need to look at a broader population of individuals in British Columbia with varying risks of complications from COVID-19 infection.

Before the study, a common view was that patients aged 70 and older would benefit from the drug, said Dr. Dormuth. “Our study, which accounted for medical conditions related to an individual’s vulnerability to complications, showed that older age on its own was not a reason to use nirmatrelvir and ritonavir once relevant medical conditions were taken into consideration.”

The researchers are working on a study to identify with greater specificity which comorbid conditions are most associated with nirmatrelvir-ritonavir effectiveness, he added. “It could be that a relatively small number of conditions can be used to identify most individuals who would benefit from the drug.”
 

‘Signal toward benefit’

Commenting on the findings for this news organization, Abhijit Duggal, MD, vice chair of critical care at the Cleveland Clinic, who was not involved in this study, said, “I’m always very wary when we look at observational data and we start saying the effectiveness is not really as high as was seen in other studies. We are seeing an effect with all these studies that seems to be in the right direction.

“Having said that,” he added, “is the effect going to be potentially more in patients at higher risk? Absolutely. I think these postmarket studies are really showing that after vaccination, if someone does get infected, this is a secondary option available to us that can prevent progression of the disease, which would likely be more severe in immunocompromised patients.”

Dr. Duggal was a coinvestigator on a recent study of more than 68,000 patients that showed that nirmatrelvir-ritonavir or molnupiravir was associated with reductions in mortality and hospitalization in nonhospitalized patients infected with the Omicron variant, regardless of age, race and ethnicity, virus strain, vaccination status, previous infection status, or coexisting conditions.

“In all groups, there was a signal toward benefit,” said Dr. Duggal. “These studies tell us that these drugs do remain valid options. But their use needs to be discussed on a case-by-case basis with patients we feel are deteriorating or at a higher risk because of underlying disease processes.”

The study was supported by funding from the British Columbia Ministry of Health. Dr. Dormuth and Dr. Duggal report no relevant financial relationships.

A version of this article appeared on Medscape.com.

Nirmatrelvir-ritonavir (Paxlovid) is associated with a reduced risk for death or hospitalization in the most extremely vulnerable patients with COVID-19, new research suggests.

In a cohort study from British Columbia that included nearly 7,000 patients with COVID-19, nirmatrelvir-ritonavir was associated with a 2.5% reduction in risk for death or emergency hospitalization in clinically extremely vulnerable (CEV) patients who were severely immunocompromised. No significant benefit was observed in patients who were not immunocompromised.

“This finding could help substantially limit unnecessary use of nirmatrelvir and ritonavir in older, otherwise healthy individuals,” lead author Colin R. Dormuth, ScD, associate professor of anesthesiology, pharmacology, and therapeutics at the University of British Columbia, Vancouver, told this news organization. “Another finding that was surprising and might help place the role of nirmatrelvir and ritonavir in context is that even in severely immunocompromised individuals who did not take [the drug], the risk of death or hospitalization with COVID-19 was less than 4% in our study population.”

The study was published online in JAMA Network Open.
 

Who benefits?

The investigators analyzed medical records for 6,866 patients in British Columbia (median age, 70 years; 57% women) who presented between Feb. 1, 2022, and Feb. 3, 2023. Eligible patients belonged to one of four higher-risk groups who received priority for COVID-19 vaccination.

Two groups included CEV patients who were severely (CEV1) or moderately (CEV2) immunocompromised. The CEV3 group was not immunocompromised but had medical conditions associated with a high risk for complications from COVID-19. A fourth expanded eligibility (EXEL) group included higher-risk patients who were not in one of the other groups, such as unvaccinated patients older than age 70 years.

The investigators matched treated patients to untreated patients in the same vulnerability group according to age, sex, and month of infection. The primary outcome was death from any cause or emergency hospitalization with COVID-19 within 28 days.

Treatment with nirmatrelvir-ritonavir was associated with statistically significant relative reductions in the primary outcome, compared with no treatment, for patients in the CEV1 (risk difference, −2.5%) and CEV2 (RD, −1.7%) groups. In the CEV3 group, the RD of −1.3% was not statistically significant. In the EXEL group, treatment was associated with a higher risk for the primary outcome (RD, 1.0%), but the result was not statistically significant.

The results were “robust across sex and older vs. younger age,” the authors note. “No reduction in the primary outcome was observed in lower-risk individuals, including those aged 70 years or older without serious comorbidities.”

The combination of nirmatrelvir-ritonavir was approved for use in Canada based on interim efficacy and safety data from the Evaluation of Inhibition for COVID-19 in High-Risk Patients (EPIC-HR) trial, said Dr. Dormuth.

British Columbia’s eligibility criteria for nirmatrelvir-ritonavir coverage differ substantially from the criteria for participants in the EPIC-HR trial, he noted. Those patients were unvaccinated, had no natural immunity from a previous COVID-19 infection, and were infected with COVID-19 variants that were different from those now circulating. The current study was prompted by the need to look at a broader population of individuals in British Columbia with varying risks of complications from COVID-19 infection.

Before the study, a common view was that patients aged 70 and older would benefit from the drug, said Dr. Dormuth. “Our study, which accounted for medical conditions related to an individual’s vulnerability to complications, showed that older age on its own was not a reason to use nirmatrelvir and ritonavir once relevant medical conditions were taken into consideration.”

The researchers are working on a study to identify with greater specificity which comorbid conditions are most associated with nirmatrelvir-ritonavir effectiveness, he added. “It could be that a relatively small number of conditions can be used to identify most individuals who would benefit from the drug.”
 

‘Signal toward benefit’

Commenting on the findings for this news organization, Abhijit Duggal, MD, vice chair of critical care at the Cleveland Clinic, who was not involved in this study, said, “I’m always very wary when we look at observational data and we start saying the effectiveness is not really as high as was seen in other studies. We are seeing an effect with all these studies that seems to be in the right direction.

“Having said that,” he added, “is the effect going to be potentially more in patients at higher risk? Absolutely. I think these postmarket studies are really showing that after vaccination, if someone does get infected, this is a secondary option available to us that can prevent progression of the disease, which would likely be more severe in immunocompromised patients.”

Dr. Duggal was a coinvestigator on a recent study of more than 68,000 patients that showed that nirmatrelvir-ritonavir or molnupiravir was associated with reductions in mortality and hospitalization in nonhospitalized patients infected with the Omicron variant, regardless of age, race and ethnicity, virus strain, vaccination status, previous infection status, or coexisting conditions.

“In all groups, there was a signal toward benefit,” said Dr. Duggal. “These studies tell us that these drugs do remain valid options. But their use needs to be discussed on a case-by-case basis with patients we feel are deteriorating or at a higher risk because of underlying disease processes.”

The study was supported by funding from the British Columbia Ministry of Health. Dr. Dormuth and Dr. Duggal report no relevant financial relationships.

A version of this article appeared on Medscape.com.

Non-hypoxemic patients with intermediate risk of pulmonary embolism showed no added benefit from supplemental oxygen compared with ambient oxygen in a pilot study of 70 individuals.

Anticoagulation monotherapy is the standard of care for patients with intermediate-risk pulmonary embolism (PE), but persistent short-term complication rates may approach 10%, wrote Deisy Barrios, MD, of Hospital Ramón y Cajal (IRYCIS), Madrid, and colleagues. Additional strategies are needed, and the use of supplemental oxygen in non-hypoxemic patients with intermediate-risk PE has not been explored, they said.

In a study published in the journal Chest, the researchers recruited 36 women and 34 men who were non-hypoxemic with stable PE and intermediate risk, defined as echocardiographic RV enlargement. The study recruitment ended prematurely because of the COVID-19 pandemic. The mean age of the participants was 67.3 years. Patients were randomized within 24 hours of hospital admission to anticoagulation plus supplemental oxygen or anticoagulation alone. The groups were similar in echocardiographic mean RV end-diameter and RV/LV ratios at baseline.

The intervention patients received supplemental oxygen at a 35% concentration (7 L/min) continuously for 48 hours via a face mask, and through a nasal cannula during meal times.

The primary outcome was normalization of right ventricle size (defined as an RV/LV diameter ratio less than 1.0 from the subcostal or apical view) at 48 hours after randomization. Secondary outcomes included change in the right ventricle/left ventricle diameter as measured at 48 hours and 7 days after randomization compared to baseline.

The proportion of patients with an RV/LV ratio of 1.0 or less at 48 hours was not significantly different between the intervention and control groups (42.4% vs. 21.6%, P = .08). Similarly, the proportion of patients with an RV/LV ratio of 1.0 or less at 7 days was not significantly different between the groups (76% vs. 70%).

The between-group reduction in RV/LV ratio was significantly greater in the supplemental oxygen group vs. the control group from baseline to 48 hours (0.28 vs. 0.12 P = .02).

However, the within-group mean RV/LV ratio was significantly reduced in both the supplemental oxygen group and the control group compared to baseline at 48 hours and at 7 days after randomization.

None of the patients experienced hemodynamic collapse or recurrent venous thromboembolism during the follow-up period.

The findings were limited by several factors including the small sample size and open-label design, and lack of power to detect clinical outcomes, the researchers noted.

However, the results suggest that although supplemental oxygen had no significant impact of RV/LV normalization, “supplemental oxygen might increase the likelihood of reducing echocardiographic RV dilatation,” and the findings warrant a definitive clinical outcomes trial of supplemental oxygen vs. ambient air to improve outcomes in non-hypoxemic patients with intermediate-risk PE, they concluded.

The study was supported by the Instituto de Salud Carlos III. Dr. Barrios had no financial conflicts to disclose.

Non-hypoxemic patients with intermediate risk of pulmonary embolism showed no added benefit from supplemental oxygen compared with ambient oxygen in a pilot study of 70 individuals.

Anticoagulation monotherapy is the standard of care for patients with intermediate-risk pulmonary embolism (PE), but persistent short-term complication rates may approach 10%, wrote Deisy Barrios, MD, of Hospital Ramón y Cajal (IRYCIS), Madrid, and colleagues. Additional strategies are needed, and the use of supplemental oxygen in non-hypoxemic patients with intermediate-risk PE has not been explored, they said.

In a study published in the journal Chest, the researchers recruited 36 women and 34 men who were non-hypoxemic with stable PE and intermediate risk, defined as echocardiographic RV enlargement. The study recruitment ended prematurely because of the COVID-19 pandemic. The mean age of the participants was 67.3 years. Patients were randomized within 24 hours of hospital admission to anticoagulation plus supplemental oxygen or anticoagulation alone. The groups were similar in echocardiographic mean RV end-diameter and RV/LV ratios at baseline.

The intervention patients received supplemental oxygen at a 35% concentration (7 L/min) continuously for 48 hours via a face mask, and through a nasal cannula during meal times.

The primary outcome was normalization of right ventricle size (defined as an RV/LV diameter ratio less than 1.0 from the subcostal or apical view) at 48 hours after randomization. Secondary outcomes included change in the right ventricle/left ventricle diameter as measured at 48 hours and 7 days after randomization compared to baseline.

The proportion of patients with an RV/LV ratio of 1.0 or less at 48 hours was not significantly different between the intervention and control groups (42.4% vs. 21.6%, P = .08). Similarly, the proportion of patients with an RV/LV ratio of 1.0 or less at 7 days was not significantly different between the groups (76% vs. 70%).

The between-group reduction in RV/LV ratio was significantly greater in the supplemental oxygen group vs. the control group from baseline to 48 hours (0.28 vs. 0.12 P = .02).

However, the within-group mean RV/LV ratio was significantly reduced in both the supplemental oxygen group and the control group compared to baseline at 48 hours and at 7 days after randomization.

None of the patients experienced hemodynamic collapse or recurrent venous thromboembolism during the follow-up period.

The findings were limited by several factors including the small sample size and open-label design, and lack of power to detect clinical outcomes, the researchers noted.

However, the results suggest that although supplemental oxygen had no significant impact of RV/LV normalization, “supplemental oxygen might increase the likelihood of reducing echocardiographic RV dilatation,” and the findings warrant a definitive clinical outcomes trial of supplemental oxygen vs. ambient air to improve outcomes in non-hypoxemic patients with intermediate-risk PE, they concluded.

The study was supported by the Instituto de Salud Carlos III. Dr. Barrios had no financial conflicts to disclose.

Non-hypoxemic patients with intermediate risk of pulmonary embolism showed no added benefit from supplemental oxygen compared with ambient oxygen in a pilot study of 70 individuals.

Anticoagulation monotherapy is the standard of care for patients with intermediate-risk pulmonary embolism (PE), but persistent short-term complication rates may approach 10%, wrote Deisy Barrios, MD, of Hospital Ramón y Cajal (IRYCIS), Madrid, and colleagues. Additional strategies are needed, and the use of supplemental oxygen in non-hypoxemic patients with intermediate-risk PE has not been explored, they said.

In a study published in the journal Chest, the researchers recruited 36 women and 34 men who were non-hypoxemic with stable PE and intermediate risk, defined as echocardiographic RV enlargement. The study recruitment ended prematurely because of the COVID-19 pandemic. The mean age of the participants was 67.3 years. Patients were randomized within 24 hours of hospital admission to anticoagulation plus supplemental oxygen or anticoagulation alone. The groups were similar in echocardiographic mean RV end-diameter and RV/LV ratios at baseline.

The intervention patients received supplemental oxygen at a 35% concentration (7 L/min) continuously for 48 hours via a face mask, and through a nasal cannula during meal times.

The primary outcome was normalization of right ventricle size (defined as an RV/LV diameter ratio less than 1.0 from the subcostal or apical view) at 48 hours after randomization. Secondary outcomes included change in the right ventricle/left ventricle diameter as measured at 48 hours and 7 days after randomization compared to baseline.

The proportion of patients with an RV/LV ratio of 1.0 or less at 48 hours was not significantly different between the intervention and control groups (42.4% vs. 21.6%, P = .08). Similarly, the proportion of patients with an RV/LV ratio of 1.0 or less at 7 days was not significantly different between the groups (76% vs. 70%).

The between-group reduction in RV/LV ratio was significantly greater in the supplemental oxygen group vs. the control group from baseline to 48 hours (0.28 vs. 0.12 P = .02).

However, the within-group mean RV/LV ratio was significantly reduced in both the supplemental oxygen group and the control group compared to baseline at 48 hours and at 7 days after randomization.

None of the patients experienced hemodynamic collapse or recurrent venous thromboembolism during the follow-up period.

The findings were limited by several factors including the small sample size and open-label design, and lack of power to detect clinical outcomes, the researchers noted.

However, the results suggest that although supplemental oxygen had no significant impact of RV/LV normalization, “supplemental oxygen might increase the likelihood of reducing echocardiographic RV dilatation,” and the findings warrant a definitive clinical outcomes trial of supplemental oxygen vs. ambient air to improve outcomes in non-hypoxemic patients with intermediate-risk PE, they concluded.

The study was supported by the Instituto de Salud Carlos III. Dr. Barrios had no financial conflicts to disclose.

HONOLULU – What we eat and what’s in the gut may influence lung health for better or worse, suggest new data from an ongoing study of lung function in New York City firefighters who were at the World Trade Center site on Sept. 11, 2001, and the days immediately following the 9/11 attacks.

Among NYC firefighters enrolled in the randomized FIREHOUSE (Food Intake Restriction for Health Outcome Support and Education) study who took part in a microbiome substudy, those who followed a low-calorie, Mediterranean-style diet had higher levels in stools samples at 6 months of Bacteroides ovatus, a bacterial species associated with protection against bowel inflammation.

In contrast, participants who followed a usual-care diet had elevated 6-month levels of a species associated with high-fat diets and inflammation, reported Rachel Lam, a predoctoral fellow in the Nolan Lab at NYU Langone Medical Center, at the annual meeting of the American College of Chest Physicians (CHEST).

“Overall, we found that in our validation cohort, Bacteroides ovatus was increased in the LoCalMed arm after 6 months, and this bacterial species is associated with fewer negative health effects,” she said.

Ms. Lam noted that in a murine model of high-fat diets, mice gavaged with Bacteroides ovatus had reductions in body mass index and decreased serum LDL cholesterol and triglyceride levels.
 

FIREHOUSE cohort

Senior author Anna Nolan, MD, whose lab members study predictors of lung function loss in a cohort of firefighters who were exposed to the particulate matter clouding the air of lower Manhattan on 9/11 and the ensuing days, told this news organization that the findings, while preliminary, support previous research findings on potential links between intestinal microbiota and lung function.

“It’s interesting that we saw this done in other models, like mouse models and such, where certain bacteria were viewed as healthy for the system, and if they were able to bring that bacteria out in larger amounts they saw anti-inflammatory effects, so we’re hoping to mirror that and also do a mouse model,” she said.

Dr. Nolan’s group has previously shown that markers for the metabolic syndrome, inflammation, and vascular injury detected in serum samples taken within 6 months of 9/11 were predictive for later abnormal lung function. In addition, their group has found that elevated serum levels of an LDL metabolite after intense World Trade Center dust exposure is a risk factor for future impaired lung function as measured by forced expiratory volume in 1 second (FEV₁).

In the FIREHOUSE trial, 89 patients were randomly assigned either to a technology-supported educational and behavioral intervention targeting calorie restriction for weight loss while following a low-calorie Mediterranean diet, or to usual care. The usual-care arm included participants who were informed about their weight, BMI, and other standard measures at annual visits and were given general advice about healthy eating, but were not assigned to a specific diet.

Participants in the LoCalMed group had significant decreases in BMI and increases in FEV₁, compared with those in the usual-care group. In addition, the LoCalMed group had improved vascular health, better dietary habits, decreases in fats and calories from sweets, and decreases in inflammation as measured by a lower white blood cell count.
 

Microbiome substudy

At CHEST 2023, Ms. Lam reported on microbiome pilot and validation substudies of FIREHOUSE.

The pilot study included five patients in each arm. The validation sample included 15 participants in the Mediterranean diet group and 16 in the usual-care diet group.

Each participant’s microbiome was assessed with genomic sequencing with sequences aligned to a bacterial database.  The number and diversity of bacterial species in each sample were determined with the Chao1 Index and Shannon Index, respectively.

There were no significant differences among the study groups in mean age, exposure at the World Trade Center site, or years of service.

Although bacterial diversity did not differ between the study arms either at baseline or at 6 months, in both groups it significantly decreased over time (P = .02 in the pilot, P < .0001 in the validation arm).

In the pilot study, there was an increase over 6 months in the usual care arm only of Bilophila wadsworthia, a species associated with high-fat diets and inflammation.

In the validation study, patients in the LoCalMed arm had significant reductions in Ruminococcaceae (P = .015) and increases in both Bacteroides ovatus (P = .03) and Alistipes shahii (P = .038), a recently identified species with uncertain protective or pathogenic potential.

In contrast, there were no significant increases in species in the usual-care group, but there were significant declines in several other bacterial species; Ms.Lam, however, did not say whether these changes had clinical significance. “Future studies will assess microbial association with clinical outcomes,” Ms. Lam said.
 

Confounding factors

Samuel Evans, MD, a pulmonologist at Straub Medical Center in Honolulu who moderated the oral abstract session where the data were presented, commented that the data are interesting but added that associations are difficult to determine given the heterogeneity of exposures that firefighters encounter.

“I think it’s interesting that clearly diet is influencing the type of bacteria in the biome in the gut, and perhaps some are favorable, and some are not favorable,” he told this news organization “We already know that the Mediterranean diet is associated with better health outcomes, so it makes sense, but can we tease out in the microbiome which bacteria are harmful and which are helpful.”

He noted that there are a lot of confounding factors and that “it’s hard to find the right signal when you have so many variables.”

The FIREHOUSE study is supported by the Centers for Disease Control and Prevention’s National Institute of Occupational Safety & Health and the National Heart, Lung, and Blood Institute. Ms. Lam, Dr. Nolan, and Dr. Evans report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

HONOLULU – What we eat and what’s in the gut may influence lung health for better or worse, suggest new data from an ongoing study of lung function in New York City firefighters who were at the World Trade Center site on Sept. 11, 2001, and the days immediately following the 9/11 attacks.

Among NYC firefighters enrolled in the randomized FIREHOUSE (Food Intake Restriction for Health Outcome Support and Education) study who took part in a microbiome substudy, those who followed a low-calorie, Mediterranean-style diet had higher levels in stools samples at 6 months of Bacteroides ovatus, a bacterial species associated with protection against bowel inflammation.

In contrast, participants who followed a usual-care diet had elevated 6-month levels of a species associated with high-fat diets and inflammation, reported Rachel Lam, a predoctoral fellow in the Nolan Lab at NYU Langone Medical Center, at the annual meeting of the American College of Chest Physicians (CHEST).

“Overall, we found that in our validation cohort, Bacteroides ovatus was increased in the LoCalMed arm after 6 months, and this bacterial species is associated with fewer negative health effects,” she said.

Ms. Lam noted that in a murine model of high-fat diets, mice gavaged with Bacteroides ovatus had reductions in body mass index and decreased serum LDL cholesterol and triglyceride levels.
 

FIREHOUSE cohort

Senior author Anna Nolan, MD, whose lab members study predictors of lung function loss in a cohort of firefighters who were exposed to the particulate matter clouding the air of lower Manhattan on 9/11 and the ensuing days, told this news organization that the findings, while preliminary, support previous research findings on potential links between intestinal microbiota and lung function.

“It’s interesting that we saw this done in other models, like mouse models and such, where certain bacteria were viewed as healthy for the system, and if they were able to bring that bacteria out in larger amounts they saw anti-inflammatory effects, so we’re hoping to mirror that and also do a mouse model,” she said.

Dr. Nolan’s group has previously shown that markers for the metabolic syndrome, inflammation, and vascular injury detected in serum samples taken within 6 months of 9/11 were predictive for later abnormal lung function. In addition, their group has found that elevated serum levels of an LDL metabolite after intense World Trade Center dust exposure is a risk factor for future impaired lung function as measured by forced expiratory volume in 1 second (FEV₁).

In the FIREHOUSE trial, 89 patients were randomly assigned either to a technology-supported educational and behavioral intervention targeting calorie restriction for weight loss while following a low-calorie Mediterranean diet, or to usual care. The usual-care arm included participants who were informed about their weight, BMI, and other standard measures at annual visits and were given general advice about healthy eating, but were not assigned to a specific diet.

Participants in the LoCalMed group had significant decreases in BMI and increases in FEV₁, compared with those in the usual-care group. In addition, the LoCalMed group had improved vascular health, better dietary habits, decreases in fats and calories from sweets, and decreases in inflammation as measured by a lower white blood cell count.
 

Microbiome substudy

At CHEST 2023, Ms. Lam reported on microbiome pilot and validation substudies of FIREHOUSE.

The pilot study included five patients in each arm. The validation sample included 15 participants in the Mediterranean diet group and 16 in the usual-care diet group.

Each participant’s microbiome was assessed with genomic sequencing with sequences aligned to a bacterial database.  The number and diversity of bacterial species in each sample were determined with the Chao1 Index and Shannon Index, respectively.

There were no significant differences among the study groups in mean age, exposure at the World Trade Center site, or years of service.

Although bacterial diversity did not differ between the study arms either at baseline or at 6 months, in both groups it significantly decreased over time (P = .02 in the pilot, P < .0001 in the validation arm).

In the pilot study, there was an increase over 6 months in the usual care arm only of Bilophila wadsworthia, a species associated with high-fat diets and inflammation.

In the validation study, patients in the LoCalMed arm had significant reductions in Ruminococcaceae (P = .015) and increases in both Bacteroides ovatus (P = .03) and Alistipes shahii (P = .038), a recently identified species with uncertain protective or pathogenic potential.

In contrast, there were no significant increases in species in the usual-care group, but there were significant declines in several other bacterial species; Ms.Lam, however, did not say whether these changes had clinical significance. “Future studies will assess microbial association with clinical outcomes,” Ms. Lam said.
 

Confounding factors

Samuel Evans, MD, a pulmonologist at Straub Medical Center in Honolulu who moderated the oral abstract session where the data were presented, commented that the data are interesting but added that associations are difficult to determine given the heterogeneity of exposures that firefighters encounter.

“I think it’s interesting that clearly diet is influencing the type of bacteria in the biome in the gut, and perhaps some are favorable, and some are not favorable,” he told this news organization “We already know that the Mediterranean diet is associated with better health outcomes, so it makes sense, but can we tease out in the microbiome which bacteria are harmful and which are helpful.”

He noted that there are a lot of confounding factors and that “it’s hard to find the right signal when you have so many variables.”

The FIREHOUSE study is supported by the Centers for Disease Control and Prevention’s National Institute of Occupational Safety & Health and the National Heart, Lung, and Blood Institute. Ms. Lam, Dr. Nolan, and Dr. Evans report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

HONOLULU – What we eat and what’s in the gut may influence lung health for better or worse, suggest new data from an ongoing study of lung function in New York City firefighters who were at the World Trade Center site on Sept. 11, 2001, and the days immediately following the 9/11 attacks.

Among NYC firefighters enrolled in the randomized FIREHOUSE (Food Intake Restriction for Health Outcome Support and Education) study who took part in a microbiome substudy, those who followed a low-calorie, Mediterranean-style diet had higher levels in stools samples at 6 months of Bacteroides ovatus, a bacterial species associated with protection against bowel inflammation.

In contrast, participants who followed a usual-care diet had elevated 6-month levels of a species associated with high-fat diets and inflammation, reported Rachel Lam, a predoctoral fellow in the Nolan Lab at NYU Langone Medical Center, at the annual meeting of the American College of Chest Physicians (CHEST).

“Overall, we found that in our validation cohort, Bacteroides ovatus was increased in the LoCalMed arm after 6 months, and this bacterial species is associated with fewer negative health effects,” she said.

Ms. Lam noted that in a murine model of high-fat diets, mice gavaged with Bacteroides ovatus had reductions in body mass index and decreased serum LDL cholesterol and triglyceride levels.
 

FIREHOUSE cohort

Senior author Anna Nolan, MD, whose lab members study predictors of lung function loss in a cohort of firefighters who were exposed to the particulate matter clouding the air of lower Manhattan on 9/11 and the ensuing days, told this news organization that the findings, while preliminary, support previous research findings on potential links between intestinal microbiota and lung function.

“It’s interesting that we saw this done in other models, like mouse models and such, where certain bacteria were viewed as healthy for the system, and if they were able to bring that bacteria out in larger amounts they saw anti-inflammatory effects, so we’re hoping to mirror that and also do a mouse model,” she said.

Dr. Nolan’s group has previously shown that markers for the metabolic syndrome, inflammation, and vascular injury detected in serum samples taken within 6 months of 9/11 were predictive for later abnormal lung function. In addition, their group has found that elevated serum levels of an LDL metabolite after intense World Trade Center dust exposure is a risk factor for future impaired lung function as measured by forced expiratory volume in 1 second (FEV₁).

In the FIREHOUSE trial, 89 patients were randomly assigned either to a technology-supported educational and behavioral intervention targeting calorie restriction for weight loss while following a low-calorie Mediterranean diet, or to usual care. The usual-care arm included participants who were informed about their weight, BMI, and other standard measures at annual visits and were given general advice about healthy eating, but were not assigned to a specific diet.

Participants in the LoCalMed group had significant decreases in BMI and increases in FEV₁, compared with those in the usual-care group. In addition, the LoCalMed group had improved vascular health, better dietary habits, decreases in fats and calories from sweets, and decreases in inflammation as measured by a lower white blood cell count.
 

Microbiome substudy

At CHEST 2023, Ms. Lam reported on microbiome pilot and validation substudies of FIREHOUSE.

The pilot study included five patients in each arm. The validation sample included 15 participants in the Mediterranean diet group and 16 in the usual-care diet group.

Each participant’s microbiome was assessed with genomic sequencing with sequences aligned to a bacterial database.  The number and diversity of bacterial species in each sample were determined with the Chao1 Index and Shannon Index, respectively.

There were no significant differences among the study groups in mean age, exposure at the World Trade Center site, or years of service.

Although bacterial diversity did not differ between the study arms either at baseline or at 6 months, in both groups it significantly decreased over time (P = .02 in the pilot, P < .0001 in the validation arm).

In the pilot study, there was an increase over 6 months in the usual care arm only of Bilophila wadsworthia, a species associated with high-fat diets and inflammation.

In the validation study, patients in the LoCalMed arm had significant reductions in Ruminococcaceae (P = .015) and increases in both Bacteroides ovatus (P = .03) and Alistipes shahii (P = .038), a recently identified species with uncertain protective or pathogenic potential.

In contrast, there were no significant increases in species in the usual-care group, but there were significant declines in several other bacterial species; Ms.Lam, however, did not say whether these changes had clinical significance. “Future studies will assess microbial association with clinical outcomes,” Ms. Lam said.
 

Confounding factors

Samuel Evans, MD, a pulmonologist at Straub Medical Center in Honolulu who moderated the oral abstract session where the data were presented, commented that the data are interesting but added that associations are difficult to determine given the heterogeneity of exposures that firefighters encounter.

“I think it’s interesting that clearly diet is influencing the type of bacteria in the biome in the gut, and perhaps some are favorable, and some are not favorable,” he told this news organization “We already know that the Mediterranean diet is associated with better health outcomes, so it makes sense, but can we tease out in the microbiome which bacteria are harmful and which are helpful.”

He noted that there are a lot of confounding factors and that “it’s hard to find the right signal when you have so many variables.”

The FIREHOUSE study is supported by the Centers for Disease Control and Prevention’s National Institute of Occupational Safety & Health and the National Heart, Lung, and Blood Institute. Ms. Lam, Dr. Nolan, and Dr. Evans report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

With the emergence of pirfenidone and nintedanib over the past decade or so, pulmonologists now have at their disposal two breakthrough antifibrotic agents for the treatment of idiopathic pulmonary fibrosis.

Artfoliophoto/Thinkstock

But these two drugs have a number of shortcomings that a host of investigative agents are aiming to address. For one, while pirfenidone and nintedanib have been shown to slow disease progression and improve symptoms, they don’t stop or reverse the disease. Also, a large number of patients with IPF don’t tolerate these drugs well. And, their high cost is a barrier for many patients.

Joyce Lee, MD

“There are no curative therapies that improve lung function or improve symptoms, so there remains a very large unmet need in terms of therapies or interventions that have better efficacy, better long-term tolerability, and that improve symptoms and quality of life for our patients with IPF disease,” said Joyce Lee, MD, associate professor of medicine–pulmonary at the University of Colorado at Denver, Aurora, and senior medical adviser for research and health care quality for the Pulmonary Fibrosis Foundation.

The National Institutes of Health estimates that more than 30,000 new cases of IPF are diagnosed in the United States annually, and as many as 3 million people have the disease worldwide. The 5-year survival rate is less than 40% after diagnosis. Bloomberg News reported that more than 80 pharmaceutical companies are working on IPF treatments. iHealthcareAnalyst estimates the global market for IPF will reach $10.1 billion by 2029 thanks to rapidly increasing prevalence and incidence with age, premium-priced drugs, and rapid approval of new treatments.
 

The perils of phase 3 studies

A search on ClinicalTrials.gov turned up 89 investigative IPF treatments in human trials. However, the search for alternatives can be perilous. “In the field, we have gotten used to promising phase 2 studies that failed in the phase 3 stage of development,” Dr. Lee said. “I don’t hold my breath these days just in terms of trying to predict whether or not the efficacy will be present in the phase 3 clinical trial.”

Three notable phase 3 flops include the ISABELA 1 and 2 trials of the autotaxin inhibitor ziritaxestat, which failed to meet their primary endpoint and were halted early (JAMA. 2023;329:1567-78). The phase 3 ZEPHYRUS-1 trial failed to show any benefit of pamrevlumab to improve percent predicted force vital capacity (ppFVC) at week 48, causing discontinuation of a second phase 3 trial. The phase 3 STARSCAPE-OLE study of intravenous recombinant human pentraxin-2 was terminated earlier this year when the sponsor, Hoffmann-LaRoche, decided it was unable to meet its primary objective (NCT04594707).

In the meantime, these six other phase 3 programs in IPF are still in the field:

Anlotinib. A phase 2 and 3 trial in China is evaluating 1-year outcomes of once-daily oral anlotinib for treatment of IPF/progressive fibrosis-interstitial lung disease (PF-ILDS) (NCT05828953). Anlotinib is a tyrosine kinase inhibitor (TKI) that targets four factors: vascular endothelial growth factor receptor (VEGR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptors (PDGFR), and c-kit. It’s approved in China as a third-line therapy for non–small cell lung cancer (NSCLC).

BI 101550. Enrollment in the FIBRONEER-IPF trial commenced last fall (NCT05321069), with completion scheduled for late next year. BI 1015550 is an oral phosphodiesterase 4B (PDE4B) inhibitor. FIBRONEER-ILD is a separate phase 3 trial in fibrosing idiopathic lung disease (NCT05321082). In both trials, the primary endpoint is the absolute change from baseline in FVC at week 52.

BMS-986278. Results of a phase 2 trial showed that twice-daily treatment with oral BMS-986278 60 mg over 26 weeks reduced the rate of decline in  ppFVC by 69% vs. placebo. The phase 3 ALOFT trial has been approved but hasn’t yet started recruiting patients (NCT06003426). BMS-986278 is a lysophosphatidic acid receptor 1 (LPA1) antagonist.

Lanxoprazole. Commonly used to treat and prevent gastrointestinal problems like stomach ulcers and esophagitis, this oral proton pump inhibitor (PPI) is the focus of a trial in the United Kingdom evaluating if PPIs can slow the progression of IPF (NCT04965298).

N-acetylcysteine (NAC). The PRECISIONS trial is evaluating the effect of NAC plus standard-of-care treatment in IPF patients who have the TOLLIP rs3750910 TT genotype (NCT04300920). Participants receive 600 mg NAC orally or matched placebo three times daily for 24 months. Trial completion is scheduled for 2025.

Treprostinil. Already approved to treat pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease, inhaled Treprostinil is the subject of the TETON 1 and 2 trials evaluating its impact on ppFVC after 52 weeks of treatment (NCT04708782, NCT05255991).
 

Phase 2 candidates

The primary endpoint in most of the phase 2 trials is change in ppFVC capacity from baseline to week 24. The following investigative therapies are in phase 2 trials:

Bexotegrast (PLN-74809), an oral, small molecule, dual-selective inhibitor of alphav/beta6 and alphav/beta1  (NCT04396756).

BBT-877, described as a potent autotaxin (ATX) inhibitor, demonstrated its ability to inhibit lysophosphatidic acid (LPA) production by as much as 90 percent (NCT05483907).

CC-90001, an oral, once-daily c-Jun N-terminal kinases (JNK) inhibitor. JNKs have been implicated in the underlying mechanisms of fibrosis, including epithelial cell death, inflammation and polarization of profibrotic macrophages, fibroblast activation, and collagen production (NCT03142191).

C21 targets the underlying fibrosis in IPF by stimulating the protective arm of the renin-angiotensin system. It also has an upstream effect by promoting alveolar repair by which it can reduce fibrosis formation, stabilize disease, and increase lung capacity (NCT04533022).

CSL312 (garadacimab) is a humanized anti-FXIIa monoclonal antibody administrated intravenously (NCT05130970).

Cudetaxestat, a noncompetitive autotaxin inhibitor (NCT05373914).

Bersiposocin/DWN12088, an inhibitor of prolyl-tRNA synthetase 1 (PARS1), which is suspected to control the pathologic accumulation of collagen containing high amounts of proline in fibrotic diseases (NCT05389215).

ENV-101, a small-molecule inhibitor of the Hedgehog (Hh) signaling pathway, which plays a key role in IPF. This agent was originally developed to target Hh-driven cancers (NCT04968574).

GKT137831 (setanaxib) inhibits nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) isoforms. (NCT03865927).

HZN-825, a lysophosphatidic acid receptor 1 (LPAR1) antagonist. (NCT05032066)

Ifetroban, a potent and selective thromboxane-prostanoid receptor (TPr) antagonist, which exhibits a high affinity for TPr on platelets, vascular and airway smooth muscle, and fibroblasts, and lacks agonistic activity (NCT05571059).

INS018_055, a small-molecule, oral antifibrotic candidate notable for being the first entirely AI-generated drug to enter phase 2 trials. Trial enrollment started in October (NCT05975983, NCT05983920)

Jaktinib dihydrochloride monohydrate, an oral JAK1, JAK2, and JAK3 inhibitor (NCT04312594).

Leramistat, an anti–tumor necrosis factor (TNF) agent (NCT05951296).

LTP001, an oral, selectively deuterated form of pirfenidone designed to retain the antifibrotic and anti-inflammatory activity of pirfenidone with a differentiated pharmacokinetic profile (NCT05497284, NCT05321420).

ME-015 (suplatast tosilate) aims to stabilize ion channels in the neuronal endings in the lungs that mediate IPF-related cough (NCT05983471).

Nalbuphine, a small-molecule, dual-mechanism treatment for chronic cough in IPF. It acts as both a mu opioid receptor antagonist and a kappa opioid receptor agonist (NCT05964335). The CANAL trial, complete last year, is evaluating an extended-release formulation (NCT04030026).

NP-120 (ifenprodil), a small-molecule N-methyl-D-aspartate (NMDA) receptor antagonist, specifically targets the NMDA-type subunit 2B (GluN2B) (NCT04318704).

Orvepitant, a selective antagonist for the NK₁ receptor, is being evaluated to treat IPF-related cough (NCT05815089).

RXC007 (zelasudil), a Rho-associated coiled-coil–containing protein kinase 2 (ROCK2) selective inhibitor, was granted FDA orphan drug designation in August 2023 (NCT05570058).

Saracatinib, a selective Src kinase inhibitor originally developed for oncological indications (NCT04598919).

SHR-1906, an intravenous treatment, inhibits binding of a target protein to a variety of cytokines and growth factors, affects downstream signaling pathways, and reduces cell proliferation and migration (NCT05722964).

TTI-101, an oral, small-molecule inhibitor of signal transducer and activator of transcription (STAT3), which has been found to accumulate in the lungs of IPF patients (NCT05671835).

VAY736 (lanalumab), a BAFF-R inhibitor (NCT03287414).

Vixarelimab, a human monoclonal oncastatin M receptor beta antibody (NCT05785624).

Some investigative programs, however, didn’t make it out of phase 2. The trial evaluating inhaled GB0139, a selective functional antagonist of G-protein–coupled receptor 84, which plays a key role in fibrosis, failed to meet its primary endpoint (NCT03832946). Likewise, oral GLPG1205 failed to show a significant difference in FVC decline vs. placebo (NCT03725852). The program to develop SAR156597, also known as romilkimab, was halted (NCT02345070). ND-L02-s0201n, an siRNA oligonucleotide drug designed to inhibit heat shock protein 47 (HSP47), which regulates collagen synthesis and secretion that causes fibrosis, didn’t show the expected efficacy (NCT03538301).
 

Phase 1 trials

No fewer than 27 phase 1 trials are evaluating investigative treatments for IPF, many in the early phase or not yet recruiting. According to GlobalData, phase 1 drugs for IPF have a 66% chance of moving onto phase 2. Among the advanced phase 1 trials that have gained corporate backing are:

9MW3811, an anti–interleukin-11 monoclonal antibody IV injection (NCT05912049).

ANG-3070, an oral tyrosine kinase inhibitor targeting platelet-derived growth factor (PDGFR) alpha and beta (NCT05387785).

C106, an angiotensin II type 2 receptor agonist (NCT05427253).

HuL001, which targets alpha-enolase (NCT04540770).

LTI-03, a Caveolin-1 (Cav1)-related peptide designed to restore Cav1 expression in lung tissue (NCT05954988).

ORIN1001, a first-in-class small molecule that selectively blocks the inositol requiring enzyme 1alphase (IRE1) RNAse and blocks X-box binding protein 1 (XBP1) activation (NCT04643769).

PRS-220 is an orally inhaled anticalin protein targeting connective tissue growth factor (CTGF) (NTC05473533).

TRK-250, a single-strand, long-chain nucleic acid that selectively suppresses expression of transforming growth factor-beta 1 (TGF-beta1) protein (NCT03727802).

“While we have therapies that we’re able to give patients, we need to do more and we need to do better,” Dr. Lee said. “We’re all hopeful the next phase 3 clinical trial will be something that will help change the treatment paradigm for our patients. We’re very patient, and hopefully those that are interested in improving this treatment landscape will continue to persist.”

Dr. Lee disclosed financial relationships with Boehringer Ingelheim, Pliant Therapeutics, Blade Therapeutics, United Therapeutics, Eleven P15. and Avalyn Pharma.

With the emergence of pirfenidone and nintedanib over the past decade or so, pulmonologists now have at their disposal two breakthrough antifibrotic agents for the treatment of idiopathic pulmonary fibrosis.

Artfoliophoto/Thinkstock

But these two drugs have a number of shortcomings that a host of investigative agents are aiming to address. For one, while pirfenidone and nintedanib have been shown to slow disease progression and improve symptoms, they don’t stop or reverse the disease. Also, a large number of patients with IPF don’t tolerate these drugs well. And, their high cost is a barrier for many patients.

Joyce Lee, MD

“There are no curative therapies that improve lung function or improve symptoms, so there remains a very large unmet need in terms of therapies or interventions that have better efficacy, better long-term tolerability, and that improve symptoms and quality of life for our patients with IPF disease,” said Joyce Lee, MD, associate professor of medicine–pulmonary at the University of Colorado at Denver, Aurora, and senior medical adviser for research and health care quality for the Pulmonary Fibrosis Foundation.

The National Institutes of Health estimates that more than 30,000 new cases of IPF are diagnosed in the United States annually, and as many as 3 million people have the disease worldwide. The 5-year survival rate is less than 40% after diagnosis. Bloomberg News reported that more than 80 pharmaceutical companies are working on IPF treatments. iHealthcareAnalyst estimates the global market for IPF will reach $10.1 billion by 2029 thanks to rapidly increasing prevalence and incidence with age, premium-priced drugs, and rapid approval of new treatments.
 

The perils of phase 3 studies

A search on ClinicalTrials.gov turned up 89 investigative IPF treatments in human trials. However, the search for alternatives can be perilous. “In the field, we have gotten used to promising phase 2 studies that failed in the phase 3 stage of development,” Dr. Lee said. “I don’t hold my breath these days just in terms of trying to predict whether or not the efficacy will be present in the phase 3 clinical trial.”

Three notable phase 3 flops include the ISABELA 1 and 2 trials of the autotaxin inhibitor ziritaxestat, which failed to meet their primary endpoint and were halted early (JAMA. 2023;329:1567-78). The phase 3 ZEPHYRUS-1 trial failed to show any benefit of pamrevlumab to improve percent predicted force vital capacity (ppFVC) at week 48, causing discontinuation of a second phase 3 trial. The phase 3 STARSCAPE-OLE study of intravenous recombinant human pentraxin-2 was terminated earlier this year when the sponsor, Hoffmann-LaRoche, decided it was unable to meet its primary objective (NCT04594707).

In the meantime, these six other phase 3 programs in IPF are still in the field:

Anlotinib. A phase 2 and 3 trial in China is evaluating 1-year outcomes of once-daily oral anlotinib for treatment of IPF/progressive fibrosis-interstitial lung disease (PF-ILDS) (NCT05828953). Anlotinib is a tyrosine kinase inhibitor (TKI) that targets four factors: vascular endothelial growth factor receptor (VEGR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptors (PDGFR), and c-kit. It’s approved in China as a third-line therapy for non–small cell lung cancer (NSCLC).

BI 101550. Enrollment in the FIBRONEER-IPF trial commenced last fall (NCT05321069), with completion scheduled for late next year. BI 1015550 is an oral phosphodiesterase 4B (PDE4B) inhibitor. FIBRONEER-ILD is a separate phase 3 trial in fibrosing idiopathic lung disease (NCT05321082). In both trials, the primary endpoint is the absolute change from baseline in FVC at week 52.

BMS-986278. Results of a phase 2 trial showed that twice-daily treatment with oral BMS-986278 60 mg over 26 weeks reduced the rate of decline in  ppFVC by 69% vs. placebo. The phase 3 ALOFT trial has been approved but hasn’t yet started recruiting patients (NCT06003426). BMS-986278 is a lysophosphatidic acid receptor 1 (LPA1) antagonist.

Lanxoprazole. Commonly used to treat and prevent gastrointestinal problems like stomach ulcers and esophagitis, this oral proton pump inhibitor (PPI) is the focus of a trial in the United Kingdom evaluating if PPIs can slow the progression of IPF (NCT04965298).

N-acetylcysteine (NAC). The PRECISIONS trial is evaluating the effect of NAC plus standard-of-care treatment in IPF patients who have the TOLLIP rs3750910 TT genotype (NCT04300920). Participants receive 600 mg NAC orally or matched placebo three times daily for 24 months. Trial completion is scheduled for 2025.

Treprostinil. Already approved to treat pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease, inhaled Treprostinil is the subject of the TETON 1 and 2 trials evaluating its impact on ppFVC after 52 weeks of treatment (NCT04708782, NCT05255991).
 

Phase 2 candidates

The primary endpoint in most of the phase 2 trials is change in ppFVC capacity from baseline to week 24. The following investigative therapies are in phase 2 trials:

Bexotegrast (PLN-74809), an oral, small molecule, dual-selective inhibitor of alphav/beta6 and alphav/beta1  (NCT04396756).

BBT-877, described as a potent autotaxin (ATX) inhibitor, demonstrated its ability to inhibit lysophosphatidic acid (LPA) production by as much as 90 percent (NCT05483907).

CC-90001, an oral, once-daily c-Jun N-terminal kinases (JNK) inhibitor. JNKs have been implicated in the underlying mechanisms of fibrosis, including epithelial cell death, inflammation and polarization of profibrotic macrophages, fibroblast activation, and collagen production (NCT03142191).

C21 targets the underlying fibrosis in IPF by stimulating the protective arm of the renin-angiotensin system. It also has an upstream effect by promoting alveolar repair by which it can reduce fibrosis formation, stabilize disease, and increase lung capacity (NCT04533022).

CSL312 (garadacimab) is a humanized anti-FXIIa monoclonal antibody administrated intravenously (NCT05130970).

Cudetaxestat, a noncompetitive autotaxin inhibitor (NCT05373914).

Bersiposocin/DWN12088, an inhibitor of prolyl-tRNA synthetase 1 (PARS1), which is suspected to control the pathologic accumulation of collagen containing high amounts of proline in fibrotic diseases (NCT05389215).

ENV-101, a small-molecule inhibitor of the Hedgehog (Hh) signaling pathway, which plays a key role in IPF. This agent was originally developed to target Hh-driven cancers (NCT04968574).

GKT137831 (setanaxib) inhibits nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) isoforms. (NCT03865927).

HZN-825, a lysophosphatidic acid receptor 1 (LPAR1) antagonist. (NCT05032066)

Ifetroban, a potent and selective thromboxane-prostanoid receptor (TPr) antagonist, which exhibits a high affinity for TPr on platelets, vascular and airway smooth muscle, and fibroblasts, and lacks agonistic activity (NCT05571059).

INS018_055, a small-molecule, oral antifibrotic candidate notable for being the first entirely AI-generated drug to enter phase 2 trials. Trial enrollment started in October (NCT05975983, NCT05983920)

Jaktinib dihydrochloride monohydrate, an oral JAK1, JAK2, and JAK3 inhibitor (NCT04312594).

Leramistat, an anti–tumor necrosis factor (TNF) agent (NCT05951296).

LTP001, an oral, selectively deuterated form of pirfenidone designed to retain the antifibrotic and anti-inflammatory activity of pirfenidone with a differentiated pharmacokinetic profile (NCT05497284, NCT05321420).

ME-015 (suplatast tosilate) aims to stabilize ion channels in the neuronal endings in the lungs that mediate IPF-related cough (NCT05983471).

Nalbuphine, a small-molecule, dual-mechanism treatment for chronic cough in IPF. It acts as both a mu opioid receptor antagonist and a kappa opioid receptor agonist (NCT05964335). The CANAL trial, complete last year, is evaluating an extended-release formulation (NCT04030026).

NP-120 (ifenprodil), a small-molecule N-methyl-D-aspartate (NMDA) receptor antagonist, specifically targets the NMDA-type subunit 2B (GluN2B) (NCT04318704).

Orvepitant, a selective antagonist for the NK₁ receptor, is being evaluated to treat IPF-related cough (NCT05815089).

RXC007 (zelasudil), a Rho-associated coiled-coil–containing protein kinase 2 (ROCK2) selective inhibitor, was granted FDA orphan drug designation in August 2023 (NCT05570058).

Saracatinib, a selective Src kinase inhibitor originally developed for oncological indications (NCT04598919).

SHR-1906, an intravenous treatment, inhibits binding of a target protein to a variety of cytokines and growth factors, affects downstream signaling pathways, and reduces cell proliferation and migration (NCT05722964).

TTI-101, an oral, small-molecule inhibitor of signal transducer and activator of transcription (STAT3), which has been found to accumulate in the lungs of IPF patients (NCT05671835).

VAY736 (lanalumab), a BAFF-R inhibitor (NCT03287414).

Vixarelimab, a human monoclonal oncastatin M receptor beta antibody (NCT05785624).

Some investigative programs, however, didn’t make it out of phase 2. The trial evaluating inhaled GB0139, a selective functional antagonist of G-protein–coupled receptor 84, which plays a key role in fibrosis, failed to meet its primary endpoint (NCT03832946). Likewise, oral GLPG1205 failed to show a significant difference in FVC decline vs. placebo (NCT03725852). The program to develop SAR156597, also known as romilkimab, was halted (NCT02345070). ND-L02-s0201n, an siRNA oligonucleotide drug designed to inhibit heat shock protein 47 (HSP47), which regulates collagen synthesis and secretion that causes fibrosis, didn’t show the expected efficacy (NCT03538301).
 

Phase 1 trials

No fewer than 27 phase 1 trials are evaluating investigative treatments for IPF, many in the early phase or not yet recruiting. According to GlobalData, phase 1 drugs for IPF have a 66% chance of moving onto phase 2. Among the advanced phase 1 trials that have gained corporate backing are:

9MW3811, an anti–interleukin-11 monoclonal antibody IV injection (NCT05912049).

ANG-3070, an oral tyrosine kinase inhibitor targeting platelet-derived growth factor (PDGFR) alpha and beta (NCT05387785).

C106, an angiotensin II type 2 receptor agonist (NCT05427253).

HuL001, which targets alpha-enolase (NCT04540770).

LTI-03, a Caveolin-1 (Cav1)-related peptide designed to restore Cav1 expression in lung tissue (NCT05954988).

ORIN1001, a first-in-class small molecule that selectively blocks the inositol requiring enzyme 1alphase (IRE1) RNAse and blocks X-box binding protein 1 (XBP1) activation (NCT04643769).

PRS-220 is an orally inhaled anticalin protein targeting connective tissue growth factor (CTGF) (NTC05473533).

TRK-250, a single-strand, long-chain nucleic acid that selectively suppresses expression of transforming growth factor-beta 1 (TGF-beta1) protein (NCT03727802).

“While we have therapies that we’re able to give patients, we need to do more and we need to do better,” Dr. Lee said. “We’re all hopeful the next phase 3 clinical trial will be something that will help change the treatment paradigm for our patients. We’re very patient, and hopefully those that are interested in improving this treatment landscape will continue to persist.”

Dr. Lee disclosed financial relationships with Boehringer Ingelheim, Pliant Therapeutics, Blade Therapeutics, United Therapeutics, Eleven P15. and Avalyn Pharma.

With the emergence of pirfenidone and nintedanib over the past decade or so, pulmonologists now have at their disposal two breakthrough antifibrotic agents for the treatment of idiopathic pulmonary fibrosis.

Artfoliophoto/Thinkstock

But these two drugs have a number of shortcomings that a host of investigative agents are aiming to address. For one, while pirfenidone and nintedanib have been shown to slow disease progression and improve symptoms, they don’t stop or reverse the disease. Also, a large number of patients with IPF don’t tolerate these drugs well. And, their high cost is a barrier for many patients.

Joyce Lee, MD

“There are no curative therapies that improve lung function or improve symptoms, so there remains a very large unmet need in terms of therapies or interventions that have better efficacy, better long-term tolerability, and that improve symptoms and quality of life for our patients with IPF disease,” said Joyce Lee, MD, associate professor of medicine–pulmonary at the University of Colorado at Denver, Aurora, and senior medical adviser for research and health care quality for the Pulmonary Fibrosis Foundation.

The National Institutes of Health estimates that more than 30,000 new cases of IPF are diagnosed in the United States annually, and as many as 3 million people have the disease worldwide. The 5-year survival rate is less than 40% after diagnosis. Bloomberg News reported that more than 80 pharmaceutical companies are working on IPF treatments. iHealthcareAnalyst estimates the global market for IPF will reach $10.1 billion by 2029 thanks to rapidly increasing prevalence and incidence with age, premium-priced drugs, and rapid approval of new treatments.
 

The perils of phase 3 studies

A search on ClinicalTrials.gov turned up 89 investigative IPF treatments in human trials. However, the search for alternatives can be perilous. “In the field, we have gotten used to promising phase 2 studies that failed in the phase 3 stage of development,” Dr. Lee said. “I don’t hold my breath these days just in terms of trying to predict whether or not the efficacy will be present in the phase 3 clinical trial.”

Three notable phase 3 flops include the ISABELA 1 and 2 trials of the autotaxin inhibitor ziritaxestat, which failed to meet their primary endpoint and were halted early (JAMA. 2023;329:1567-78). The phase 3 ZEPHYRUS-1 trial failed to show any benefit of pamrevlumab to improve percent predicted force vital capacity (ppFVC) at week 48, causing discontinuation of a second phase 3 trial. The phase 3 STARSCAPE-OLE study of intravenous recombinant human pentraxin-2 was terminated earlier this year when the sponsor, Hoffmann-LaRoche, decided it was unable to meet its primary objective (NCT04594707).

In the meantime, these six other phase 3 programs in IPF are still in the field:

Anlotinib. A phase 2 and 3 trial in China is evaluating 1-year outcomes of once-daily oral anlotinib for treatment of IPF/progressive fibrosis-interstitial lung disease (PF-ILDS) (NCT05828953). Anlotinib is a tyrosine kinase inhibitor (TKI) that targets four factors: vascular endothelial growth factor receptor (VEGR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptors (PDGFR), and c-kit. It’s approved in China as a third-line therapy for non–small cell lung cancer (NSCLC).

BI 101550. Enrollment in the FIBRONEER-IPF trial commenced last fall (NCT05321069), with completion scheduled for late next year. BI 1015550 is an oral phosphodiesterase 4B (PDE4B) inhibitor. FIBRONEER-ILD is a separate phase 3 trial in fibrosing idiopathic lung disease (NCT05321082). In both trials, the primary endpoint is the absolute change from baseline in FVC at week 52.

BMS-986278. Results of a phase 2 trial showed that twice-daily treatment with oral BMS-986278 60 mg over 26 weeks reduced the rate of decline in  ppFVC by 69% vs. placebo. The phase 3 ALOFT trial has been approved but hasn’t yet started recruiting patients (NCT06003426). BMS-986278 is a lysophosphatidic acid receptor 1 (LPA1) antagonist.

Lanxoprazole. Commonly used to treat and prevent gastrointestinal problems like stomach ulcers and esophagitis, this oral proton pump inhibitor (PPI) is the focus of a trial in the United Kingdom evaluating if PPIs can slow the progression of IPF (NCT04965298).

N-acetylcysteine (NAC). The PRECISIONS trial is evaluating the effect of NAC plus standard-of-care treatment in IPF patients who have the TOLLIP rs3750910 TT genotype (NCT04300920). Participants receive 600 mg NAC orally or matched placebo three times daily for 24 months. Trial completion is scheduled for 2025.

Treprostinil. Already approved to treat pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease, inhaled Treprostinil is the subject of the TETON 1 and 2 trials evaluating its impact on ppFVC after 52 weeks of treatment (NCT04708782, NCT05255991).
 

Phase 2 candidates

The primary endpoint in most of the phase 2 trials is change in ppFVC capacity from baseline to week 24. The following investigative therapies are in phase 2 trials:

Bexotegrast (PLN-74809), an oral, small molecule, dual-selective inhibitor of alphav/beta6 and alphav/beta1  (NCT04396756).

BBT-877, described as a potent autotaxin (ATX) inhibitor, demonstrated its ability to inhibit lysophosphatidic acid (LPA) production by as much as 90 percent (NCT05483907).

CC-90001, an oral, once-daily c-Jun N-terminal kinases (JNK) inhibitor. JNKs have been implicated in the underlying mechanisms of fibrosis, including epithelial cell death, inflammation and polarization of profibrotic macrophages, fibroblast activation, and collagen production (NCT03142191).

C21 targets the underlying fibrosis in IPF by stimulating the protective arm of the renin-angiotensin system. It also has an upstream effect by promoting alveolar repair by which it can reduce fibrosis formation, stabilize disease, and increase lung capacity (NCT04533022).

CSL312 (garadacimab) is a humanized anti-FXIIa monoclonal antibody administrated intravenously (NCT05130970).

Cudetaxestat, a noncompetitive autotaxin inhibitor (NCT05373914).

Bersiposocin/DWN12088, an inhibitor of prolyl-tRNA synthetase 1 (PARS1), which is suspected to control the pathologic accumulation of collagen containing high amounts of proline in fibrotic diseases (NCT05389215).

ENV-101, a small-molecule inhibitor of the Hedgehog (Hh) signaling pathway, which plays a key role in IPF. This agent was originally developed to target Hh-driven cancers (NCT04968574).

GKT137831 (setanaxib) inhibits nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) isoforms. (NCT03865927).

HZN-825, a lysophosphatidic acid receptor 1 (LPAR1) antagonist. (NCT05032066)

Ifetroban, a potent and selective thromboxane-prostanoid receptor (TPr) antagonist, which exhibits a high affinity for TPr on platelets, vascular and airway smooth muscle, and fibroblasts, and lacks agonistic activity (NCT05571059).

INS018_055, a small-molecule, oral antifibrotic candidate notable for being the first entirely AI-generated drug to enter phase 2 trials. Trial enrollment started in October (NCT05975983, NCT05983920)

Jaktinib dihydrochloride monohydrate, an oral JAK1, JAK2, and JAK3 inhibitor (NCT04312594).

Leramistat, an anti–tumor necrosis factor (TNF) agent (NCT05951296).

LTP001, an oral, selectively deuterated form of pirfenidone designed to retain the antifibrotic and anti-inflammatory activity of pirfenidone with a differentiated pharmacokinetic profile (NCT05497284, NCT05321420).

ME-015 (suplatast tosilate) aims to stabilize ion channels in the neuronal endings in the lungs that mediate IPF-related cough (NCT05983471).

Nalbuphine, a small-molecule, dual-mechanism treatment for chronic cough in IPF. It acts as both a mu opioid receptor antagonist and a kappa opioid receptor agonist (NCT05964335). The CANAL trial, complete last year, is evaluating an extended-release formulation (NCT04030026).

NP-120 (ifenprodil), a small-molecule N-methyl-D-aspartate (NMDA) receptor antagonist, specifically targets the NMDA-type subunit 2B (GluN2B) (NCT04318704).

Orvepitant, a selective antagonist for the NK₁ receptor, is being evaluated to treat IPF-related cough (NCT05815089).

RXC007 (zelasudil), a Rho-associated coiled-coil–containing protein kinase 2 (ROCK2) selective inhibitor, was granted FDA orphan drug designation in August 2023 (NCT05570058).

Saracatinib, a selective Src kinase inhibitor originally developed for oncological indications (NCT04598919).

SHR-1906, an intravenous treatment, inhibits binding of a target protein to a variety of cytokines and growth factors, affects downstream signaling pathways, and reduces cell proliferation and migration (NCT05722964).

TTI-101, an oral, small-molecule inhibitor of signal transducer and activator of transcription (STAT3), which has been found to accumulate in the lungs of IPF patients (NCT05671835).

VAY736 (lanalumab), a BAFF-R inhibitor (NCT03287414).

Vixarelimab, a human monoclonal oncastatin M receptor beta antibody (NCT05785624).

Some investigative programs, however, didn’t make it out of phase 2. The trial evaluating inhaled GB0139, a selective functional antagonist of G-protein–coupled receptor 84, which plays a key role in fibrosis, failed to meet its primary endpoint (NCT03832946). Likewise, oral GLPG1205 failed to show a significant difference in FVC decline vs. placebo (NCT03725852). The program to develop SAR156597, also known as romilkimab, was halted (NCT02345070). ND-L02-s0201n, an siRNA oligonucleotide drug designed to inhibit heat shock protein 47 (HSP47), which regulates collagen synthesis and secretion that causes fibrosis, didn’t show the expected efficacy (NCT03538301).
 

Phase 1 trials

No fewer than 27 phase 1 trials are evaluating investigative treatments for IPF, many in the early phase or not yet recruiting. According to GlobalData, phase 1 drugs for IPF have a 66% chance of moving onto phase 2. Among the advanced phase 1 trials that have gained corporate backing are:

9MW3811, an anti–interleukin-11 monoclonal antibody IV injection (NCT05912049).

ANG-3070, an oral tyrosine kinase inhibitor targeting platelet-derived growth factor (PDGFR) alpha and beta (NCT05387785).

C106, an angiotensin II type 2 receptor agonist (NCT05427253).

HuL001, which targets alpha-enolase (NCT04540770).

LTI-03, a Caveolin-1 (Cav1)-related peptide designed to restore Cav1 expression in lung tissue (NCT05954988).

ORIN1001, a first-in-class small molecule that selectively blocks the inositol requiring enzyme 1alphase (IRE1) RNAse and blocks X-box binding protein 1 (XBP1) activation (NCT04643769).

PRS-220 is an orally inhaled anticalin protein targeting connective tissue growth factor (CTGF) (NTC05473533).

TRK-250, a single-strand, long-chain nucleic acid that selectively suppresses expression of transforming growth factor-beta 1 (TGF-beta1) protein (NCT03727802).

“While we have therapies that we’re able to give patients, we need to do more and we need to do better,” Dr. Lee said. “We’re all hopeful the next phase 3 clinical trial will be something that will help change the treatment paradigm for our patients. We’re very patient, and hopefully those that are interested in improving this treatment landscape will continue to persist.”

Dr. Lee disclosed financial relationships with Boehringer Ingelheim, Pliant Therapeutics, Blade Therapeutics, United Therapeutics, Eleven P15. and Avalyn Pharma.

HONOLULU – Among patients hospitalized with chronic obstructive pulmonary disease (COPD) exacerbations, treatment with a combination of long-acting bronchodilators was similar in safety and efficacy to a short-acting combination of albuterol and ipratropium.

The 2023 Gold Report on prevention, management, and diagnosis of COPD recommended switching to long-acting bronchodilators despite a lack of clinical evidence showing safety in patients hospitalized for COPD exacerbation, according to Rajiv Dhand, MD, who presented the new study at the annual meeting of the American College of Chest Physicians (CHEST).

“We wanted to establish the safety, because long-acting agents are approved only for use in nonhospitalized patients. We established that it was safe and that it was comparably effective, but you could give 30% lower doses. Patients don’t have to be woken up to get the medication, and there’s a better chance that all the doses will be administered to these patients. So I think that it provides convenience with similar efficacy and safety,” said Dr. Dhand, a pulmonologist and professor of medicine at the University of Tennessee, Knoxville.

The researchers randomized 60 patients to receive nebulized albuterol (2.5 mg) and ipratropium (0.5 mg) every 6 hours (short-acting group) or nebulized formoterol (20 mcg) every 12 hours and revefenacin (175 mcg) every 24 hours (long-acting group). The mean age was 63.2 years, 58.3% were male, and 65% were current smokers.

The median decrease between day 1 and day 3 in the Modified Borg Dyspnea score was 4.0 in the long-acting group (P < .001), and 2.0 in the short-acting group, though the latter was not statistically significant (P = .134). Both groups had a decrease in supplemental oxygen requirement, with no difference between the two groups. There was also no difference in the number of respiratory visits for rescue therapy.

Respiratory therapists in the audience welcomed the new evidence. “As a respiratory therapist, I feel that we should move away from giving good short acting [therapies] ... the new guidelines state that we should move away from them, but I think that physicians in general have not gone that way. The way that we’re working, giving short acting every four hours – I don’t see that it’s a benefit to our patients,” said Sharon Armstead, who attended the session and was asked to comment on the study. She is a respiratory therapist at Ascension Health and an instructor at Concordia University, Austin, Texas. Ms. Armstead has asthma, and has first-hand experience as a patient when respiratory therapists are unable to attend to the patient every 4 hours.

She suggested that continued use of short-acting therapies may be due to inertia. “It’s easier [for a physician] to click a button on [a computer screen] than to actually slow down and write the order. If we need a rescue, then we’ll call for a rescue,” Ms. Armstead said.

She anticipates that long-acting therapies will ultimately lead to better outcomes because they will increase the time that respiratory therapists can spend with patients. “That’s what we really want to do. We want to spend time with our patients and stay there and watch our patients. But if you’re just telling us to [administer a therapy] every 4 hours, it’s not really giving the patient what they need.”

Specifically, there were concerns about cardiovascular safety, but the researchers found no between-group differences.

Asked for comment, session co-moderator Brittany Duchene, MD remarked: “It’s super interesting, but I worry about the cost. From a practical perspective, it’s challenging to get those drugs placed on an outpatient basis. They are very expensive, and they’re newer [drugs], but I think overall it’s good to give less,” said Dr. Duchene, a pulmonary critical care physician at Northeastern Vermont Regional Hospital, St. Johnsbury.

A potential concern raised by one audience member is that some patients are used to frequent treatment and may grow anxious with less frequent therapy. “I think we just need some reeducation that this is like a long-acting medicine. It also decreases the burden on our respiratory therapists, which is very good,” said Dr. Duchene.

The study was funded by Mylan/Theravance Biopharma. Dr. Dhand has received research support from Theravance, Mylan, and Viatris. He has received honoraria from Teva and UpToDate. Ms. Armstead and Dr. Duchene have no relevant financial disclosures.

HONOLULU – Among patients hospitalized with chronic obstructive pulmonary disease (COPD) exacerbations, treatment with a combination of long-acting bronchodilators was similar in safety and efficacy to a short-acting combination of albuterol and ipratropium.

The 2023 Gold Report on prevention, management, and diagnosis of COPD recommended switching to long-acting bronchodilators despite a lack of clinical evidence showing safety in patients hospitalized for COPD exacerbation, according to Rajiv Dhand, MD, who presented the new study at the annual meeting of the American College of Chest Physicians (CHEST).

“We wanted to establish the safety, because long-acting agents are approved only for use in nonhospitalized patients. We established that it was safe and that it was comparably effective, but you could give 30% lower doses. Patients don’t have to be woken up to get the medication, and there’s a better chance that all the doses will be administered to these patients. So I think that it provides convenience with similar efficacy and safety,” said Dr. Dhand, a pulmonologist and professor of medicine at the University of Tennessee, Knoxville.

The researchers randomized 60 patients to receive nebulized albuterol (2.5 mg) and ipratropium (0.5 mg) every 6 hours (short-acting group) or nebulized formoterol (20 mcg) every 12 hours and revefenacin (175 mcg) every 24 hours (long-acting group). The mean age was 63.2 years, 58.3% were male, and 65% were current smokers.

The median decrease between day 1 and day 3 in the Modified Borg Dyspnea score was 4.0 in the long-acting group (P < .001), and 2.0 in the short-acting group, though the latter was not statistically significant (P = .134). Both groups had a decrease in supplemental oxygen requirement, with no difference between the two groups. There was also no difference in the number of respiratory visits for rescue therapy.

Respiratory therapists in the audience welcomed the new evidence. “As a respiratory therapist, I feel that we should move away from giving good short acting [therapies] ... the new guidelines state that we should move away from them, but I think that physicians in general have not gone that way. The way that we’re working, giving short acting every four hours – I don’t see that it’s a benefit to our patients,” said Sharon Armstead, who attended the session and was asked to comment on the study. She is a respiratory therapist at Ascension Health and an instructor at Concordia University, Austin, Texas. Ms. Armstead has asthma, and has first-hand experience as a patient when respiratory therapists are unable to attend to the patient every 4 hours.

She suggested that continued use of short-acting therapies may be due to inertia. “It’s easier [for a physician] to click a button on [a computer screen] than to actually slow down and write the order. If we need a rescue, then we’ll call for a rescue,” Ms. Armstead said.

She anticipates that long-acting therapies will ultimately lead to better outcomes because they will increase the time that respiratory therapists can spend with patients. “That’s what we really want to do. We want to spend time with our patients and stay there and watch our patients. But if you’re just telling us to [administer a therapy] every 4 hours, it’s not really giving the patient what they need.”

Specifically, there were concerns about cardiovascular safety, but the researchers found no between-group differences.

Asked for comment, session co-moderator Brittany Duchene, MD remarked: “It’s super interesting, but I worry about the cost. From a practical perspective, it’s challenging to get those drugs placed on an outpatient basis. They are very expensive, and they’re newer [drugs], but I think overall it’s good to give less,” said Dr. Duchene, a pulmonary critical care physician at Northeastern Vermont Regional Hospital, St. Johnsbury.

A potential concern raised by one audience member is that some patients are used to frequent treatment and may grow anxious with less frequent therapy. “I think we just need some reeducation that this is like a long-acting medicine. It also decreases the burden on our respiratory therapists, which is very good,” said Dr. Duchene.

The study was funded by Mylan/Theravance Biopharma. Dr. Dhand has received research support from Theravance, Mylan, and Viatris. He has received honoraria from Teva and UpToDate. Ms. Armstead and Dr. Duchene have no relevant financial disclosures.

HONOLULU – Among patients hospitalized with chronic obstructive pulmonary disease (COPD) exacerbations, treatment with a combination of long-acting bronchodilators was similar in safety and efficacy to a short-acting combination of albuterol and ipratropium.

The 2023 Gold Report on prevention, management, and diagnosis of COPD recommended switching to long-acting bronchodilators despite a lack of clinical evidence showing safety in patients hospitalized for COPD exacerbation, according to Rajiv Dhand, MD, who presented the new study at the annual meeting of the American College of Chest Physicians (CHEST).

“We wanted to establish the safety, because long-acting agents are approved only for use in nonhospitalized patients. We established that it was safe and that it was comparably effective, but you could give 30% lower doses. Patients don’t have to be woken up to get the medication, and there’s a better chance that all the doses will be administered to these patients. So I think that it provides convenience with similar efficacy and safety,” said Dr. Dhand, a pulmonologist and professor of medicine at the University of Tennessee, Knoxville.

The researchers randomized 60 patients to receive nebulized albuterol (2.5 mg) and ipratropium (0.5 mg) every 6 hours (short-acting group) or nebulized formoterol (20 mcg) every 12 hours and revefenacin (175 mcg) every 24 hours (long-acting group). The mean age was 63.2 years, 58.3% were male, and 65% were current smokers.

The median decrease between day 1 and day 3 in the Modified Borg Dyspnea score was 4.0 in the long-acting group (P < .001), and 2.0 in the short-acting group, though the latter was not statistically significant (P = .134). Both groups had a decrease in supplemental oxygen requirement, with no difference between the two groups. There was also no difference in the number of respiratory visits for rescue therapy.

Respiratory therapists in the audience welcomed the new evidence. “As a respiratory therapist, I feel that we should move away from giving good short acting [therapies] ... the new guidelines state that we should move away from them, but I think that physicians in general have not gone that way. The way that we’re working, giving short acting every four hours – I don’t see that it’s a benefit to our patients,” said Sharon Armstead, who attended the session and was asked to comment on the study. She is a respiratory therapist at Ascension Health and an instructor at Concordia University, Austin, Texas. Ms. Armstead has asthma, and has first-hand experience as a patient when respiratory therapists are unable to attend to the patient every 4 hours.

She suggested that continued use of short-acting therapies may be due to inertia. “It’s easier [for a physician] to click a button on [a computer screen] than to actually slow down and write the order. If we need a rescue, then we’ll call for a rescue,” Ms. Armstead said.

She anticipates that long-acting therapies will ultimately lead to better outcomes because they will increase the time that respiratory therapists can spend with patients. “That’s what we really want to do. We want to spend time with our patients and stay there and watch our patients. But if you’re just telling us to [administer a therapy] every 4 hours, it’s not really giving the patient what they need.”

Specifically, there were concerns about cardiovascular safety, but the researchers found no between-group differences.

Asked for comment, session co-moderator Brittany Duchene, MD remarked: “It’s super interesting, but I worry about the cost. From a practical perspective, it’s challenging to get those drugs placed on an outpatient basis. They are very expensive, and they’re newer [drugs], but I think overall it’s good to give less,” said Dr. Duchene, a pulmonary critical care physician at Northeastern Vermont Regional Hospital, St. Johnsbury.

A potential concern raised by one audience member is that some patients are used to frequent treatment and may grow anxious with less frequent therapy. “I think we just need some reeducation that this is like a long-acting medicine. It also decreases the burden on our respiratory therapists, which is very good,” said Dr. Duchene.

The study was funded by Mylan/Theravance Biopharma. Dr. Dhand has received research support from Theravance, Mylan, and Viatris. He has received honoraria from Teva and UpToDate. Ms. Armstead and Dr. Duchene have no relevant financial disclosures.

HAMBURG, GERMANY – Respiratory tract infections and asthma are 10 times more prevalent at type 2 diabetes diagnosis, compared with matched controls without a diagnosis, shows a longitudinal study looking at comorbidities both 25 years before and 25 years after a type 2 diabetes diagnosis.

About 40% of people had respiratory tract infections at the time of diagnosis with type 2 diabetes, compared with 4% who were not diagnosed. Likewise, ear, nose, and throat infections were present in 20% of people at type 2 diabetes diagnosis, compared with around 2% who were not diagnosed. A similar pattern was seen with asthma.

Taken together, the data suggest that subacute inflammation manifesting in asthma as well as the onset of asthma or an acute infection may be a precursor to a type 2 diabetes diagnosis.

“We have also found that in the years prior to diagnosis, there are associations with infections and inflammatory disorders to a much greater degree than in those people who do not get a diabetes diagnosis but who have very similar demographics,” Adrian Heald, MD, study lead and diabetes consultant from Salford (England) Royal Hospital, said in an interview.

Five years prior to diagnosis, respiratory tract infections were documented in around 23% of patients who were later diagnosed with type 2 diabetes versus 2.5% in those not diagnosed, and a similar pattern was seen for ear, nose, and throat infections and asthma. The findings suggest that patients reporting infections, in addition to other known risk factors for type 2 diabetes, might benefit from diabetes tests and early interventions, if needed.

“These novel insights offer a fascinating and fresh perspective on the onset and natural progression to type 2 diabetes and beyond, suggesting an early phase of inflammation-related disease activity long before any clinical diagnosis of type 2 diabetes is made.”

Dr. Heald points out that clinicians may intervene to stave off progression to a type 2 diabetes diagnosis in at risk patients. “At this point, an intervention could relate to lifestyle changes and involve highlighting to the patient that the morbidity they have already accumulated is suggestive of diabetes risk,” he said, adding that, “they may have dyslipidemia, hypertension, and most often excess weight so annual checks of their HbA1c, weight management, and blood pressure would need checking,” he explained.

Moderator Coen Stehouwer, MD, professor of internal medicine at Maastricht University, the Netherlands, commented, “Before clinical diagnosis of type 2 diabetes there is often a lengthy period of undiagnosed disease and before that, prediabetes, because glucose can be abnormal up to 10 years prior to clinical diagnosis.”

But he added that, “It’s not entirely clear whether the rise seen before clinical diagnosis in this study correlates with undiagnosed diabetes or prediabetes or even if it precedes type 2 diabetes – it might be because inflammation is a common origin for type 2 diabetes and various comorbidities. This might explain how they go together.”
 

Longitudinal study 25 years before and 25 years after type 2 diagnosis

Dr. Heald presented the findings at a session on inflammation in diabetes at the annual meeting of the European Association for the Study of Diabetes. The work was also published in Diabetes Therapy.

The researchers wanted to investigate the pattern of comorbidities in the years and decades prior to a diagnosis of type 2 diabetes as well as after: “With the database we used, called DARE [Diabetes Alliance for Research in England], we are able to explore phenomena longitudinally going right back to the beginning of their digital health records, looking at phenotypes over time.”

By mapping significant health issues in people who went on to develop type 2 diabetes alongside those that did not, Dr. Heald managed to develop a continuum spanning 25 years prior and 25 years after diagnosis of type 2 diabetes. The researchers also examined relationships between sociodemographic factors and longitudinal health outcomes of relevance to cardiac conditions and lower respiratory tract infections. His talk in Hamburg primarily addressed clinical phenotypes before the point of diagnosis.

Data were drawn from 1,932 people with (1,196) and without (736) type 2 diabetes. Participants in both groups were aged 66-67 years, 43%-46% were women, age at diagnosis was 50-52 years, and participants lived in Greater Manchester, United Kingdom.

In the years leading up to type 2 diagnosis, individuals consistently exhibited a considerable increase in several clinical phenotypes, reported Dr. Heald. Of note, he added, “immediately prior to type 2 diagnosis, there was a significantly greater proportion of hypertension at 35%, respiratory tract infection at 34%, heart disease at 17%, ear, nose, and throat infection at 19%, and asthma at 12%. And by comparison, the corresponding disease trajectory in matched controls was much less dramatic.”

“There is a huge difference in people who went on to receive a diagnosis of type 2 diabetes and those who did not, and not just what we’d expect – so hypertension for example or manifestations of renal disease, but importantly inflammatory disorders are more common,” he emphasized.

In addition, a larger signal for ischemic heart disease was seen just before type 2 diabetes diagnosis.

These data suggest that longitudinal clinical histories prior to a diagnosis of type 2 diabetes might offer new information, both genetic and nongenetic, about development of type 2 diabetes in relation to comorbidities.

After type 2 diabetes diagnosis, the proportion of people exhibiting coronary artery disease, hypertension, chronic kidney disease, retinopathy, and infections climbed rapidly before plateauing, reported Dr. Heald. “We also know that individuals with coronary artery disease are more highly represented in socially disadvantaged groups, and this is borne out in the data at 25 years prior and after type 2 diagnosis.”

Dr. Heald has received speaker fees or contributed to advisory boards from Lilly, AstraZeneca, Janssen, Bristol-Myers Squibb, Besins, Bayer, Sanofi, and Recordati. Research grants from Novo Nordisk, Pfizer, and Besins. Professor Stehouwer has declared no relevant conflicts.

A version of this article first appeared on Medscape.com.

HAMBURG, GERMANY – Respiratory tract infections and asthma are 10 times more prevalent at type 2 diabetes diagnosis, compared with matched controls without a diagnosis, shows a longitudinal study looking at comorbidities both 25 years before and 25 years after a type 2 diabetes diagnosis.

About 40% of people had respiratory tract infections at the time of diagnosis with type 2 diabetes, compared with 4% who were not diagnosed. Likewise, ear, nose, and throat infections were present in 20% of people at type 2 diabetes diagnosis, compared with around 2% who were not diagnosed. A similar pattern was seen with asthma.

Taken together, the data suggest that subacute inflammation manifesting in asthma as well as the onset of asthma or an acute infection may be a precursor to a type 2 diabetes diagnosis.

“We have also found that in the years prior to diagnosis, there are associations with infections and inflammatory disorders to a much greater degree than in those people who do not get a diabetes diagnosis but who have very similar demographics,” Adrian Heald, MD, study lead and diabetes consultant from Salford (England) Royal Hospital, said in an interview.

Five years prior to diagnosis, respiratory tract infections were documented in around 23% of patients who were later diagnosed with type 2 diabetes versus 2.5% in those not diagnosed, and a similar pattern was seen for ear, nose, and throat infections and asthma. The findings suggest that patients reporting infections, in addition to other known risk factors for type 2 diabetes, might benefit from diabetes tests and early interventions, if needed.

“These novel insights offer a fascinating and fresh perspective on the onset and natural progression to type 2 diabetes and beyond, suggesting an early phase of inflammation-related disease activity long before any clinical diagnosis of type 2 diabetes is made.”

Dr. Heald points out that clinicians may intervene to stave off progression to a type 2 diabetes diagnosis in at risk patients. “At this point, an intervention could relate to lifestyle changes and involve highlighting to the patient that the morbidity they have already accumulated is suggestive of diabetes risk,” he said, adding that, “they may have dyslipidemia, hypertension, and most often excess weight so annual checks of their HbA1c, weight management, and blood pressure would need checking,” he explained.

Moderator Coen Stehouwer, MD, professor of internal medicine at Maastricht University, the Netherlands, commented, “Before clinical diagnosis of type 2 diabetes there is often a lengthy period of undiagnosed disease and before that, prediabetes, because glucose can be abnormal up to 10 years prior to clinical diagnosis.”

But he added that, “It’s not entirely clear whether the rise seen before clinical diagnosis in this study correlates with undiagnosed diabetes or prediabetes or even if it precedes type 2 diabetes – it might be because inflammation is a common origin for type 2 diabetes and various comorbidities. This might explain how they go together.”
 

Longitudinal study 25 years before and 25 years after type 2 diagnosis

Dr. Heald presented the findings at a session on inflammation in diabetes at the annual meeting of the European Association for the Study of Diabetes. The work was also published in Diabetes Therapy.

The researchers wanted to investigate the pattern of comorbidities in the years and decades prior to a diagnosis of type 2 diabetes as well as after: “With the database we used, called DARE [Diabetes Alliance for Research in England], we are able to explore phenomena longitudinally going right back to the beginning of their digital health records, looking at phenotypes over time.”

By mapping significant health issues in people who went on to develop type 2 diabetes alongside those that did not, Dr. Heald managed to develop a continuum spanning 25 years prior and 25 years after diagnosis of type 2 diabetes. The researchers also examined relationships between sociodemographic factors and longitudinal health outcomes of relevance to cardiac conditions and lower respiratory tract infections. His talk in Hamburg primarily addressed clinical phenotypes before the point of diagnosis.

Data were drawn from 1,932 people with (1,196) and without (736) type 2 diabetes. Participants in both groups were aged 66-67 years, 43%-46% were women, age at diagnosis was 50-52 years, and participants lived in Greater Manchester, United Kingdom.

In the years leading up to type 2 diagnosis, individuals consistently exhibited a considerable increase in several clinical phenotypes, reported Dr. Heald. Of note, he added, “immediately prior to type 2 diagnosis, there was a significantly greater proportion of hypertension at 35%, respiratory tract infection at 34%, heart disease at 17%, ear, nose, and throat infection at 19%, and asthma at 12%. And by comparison, the corresponding disease trajectory in matched controls was much less dramatic.”

“There is a huge difference in people who went on to receive a diagnosis of type 2 diabetes and those who did not, and not just what we’d expect – so hypertension for example or manifestations of renal disease, but importantly inflammatory disorders are more common,” he emphasized.

In addition, a larger signal for ischemic heart disease was seen just before type 2 diabetes diagnosis.

These data suggest that longitudinal clinical histories prior to a diagnosis of type 2 diabetes might offer new information, both genetic and nongenetic, about development of type 2 diabetes in relation to comorbidities.

After type 2 diabetes diagnosis, the proportion of people exhibiting coronary artery disease, hypertension, chronic kidney disease, retinopathy, and infections climbed rapidly before plateauing, reported Dr. Heald. “We also know that individuals with coronary artery disease are more highly represented in socially disadvantaged groups, and this is borne out in the data at 25 years prior and after type 2 diagnosis.”

Dr. Heald has received speaker fees or contributed to advisory boards from Lilly, AstraZeneca, Janssen, Bristol-Myers Squibb, Besins, Bayer, Sanofi, and Recordati. Research grants from Novo Nordisk, Pfizer, and Besins. Professor Stehouwer has declared no relevant conflicts.

A version of this article first appeared on Medscape.com.

HAMBURG, GERMANY – Respiratory tract infections and asthma are 10 times more prevalent at type 2 diabetes diagnosis, compared with matched controls without a diagnosis, shows a longitudinal study looking at comorbidities both 25 years before and 25 years after a type 2 diabetes diagnosis.

About 40% of people had respiratory tract infections at the time of diagnosis with type 2 diabetes, compared with 4% who were not diagnosed. Likewise, ear, nose, and throat infections were present in 20% of people at type 2 diabetes diagnosis, compared with around 2% who were not diagnosed. A similar pattern was seen with asthma.

Taken together, the data suggest that subacute inflammation manifesting in asthma as well as the onset of asthma or an acute infection may be a precursor to a type 2 diabetes diagnosis.

“We have also found that in the years prior to diagnosis, there are associations with infections and inflammatory disorders to a much greater degree than in those people who do not get a diabetes diagnosis but who have very similar demographics,” Adrian Heald, MD, study lead and diabetes consultant from Salford (England) Royal Hospital, said in an interview.

Five years prior to diagnosis, respiratory tract infections were documented in around 23% of patients who were later diagnosed with type 2 diabetes versus 2.5% in those not diagnosed, and a similar pattern was seen for ear, nose, and throat infections and asthma. The findings suggest that patients reporting infections, in addition to other known risk factors for type 2 diabetes, might benefit from diabetes tests and early interventions, if needed.

“These novel insights offer a fascinating and fresh perspective on the onset and natural progression to type 2 diabetes and beyond, suggesting an early phase of inflammation-related disease activity long before any clinical diagnosis of type 2 diabetes is made.”

Dr. Heald points out that clinicians may intervene to stave off progression to a type 2 diabetes diagnosis in at risk patients. “At this point, an intervention could relate to lifestyle changes and involve highlighting to the patient that the morbidity they have already accumulated is suggestive of diabetes risk,” he said, adding that, “they may have dyslipidemia, hypertension, and most often excess weight so annual checks of their HbA1c, weight management, and blood pressure would need checking,” he explained.

Moderator Coen Stehouwer, MD, professor of internal medicine at Maastricht University, the Netherlands, commented, “Before clinical diagnosis of type 2 diabetes there is often a lengthy period of undiagnosed disease and before that, prediabetes, because glucose can be abnormal up to 10 years prior to clinical diagnosis.”

But he added that, “It’s not entirely clear whether the rise seen before clinical diagnosis in this study correlates with undiagnosed diabetes or prediabetes or even if it precedes type 2 diabetes – it might be because inflammation is a common origin for type 2 diabetes and various comorbidities. This might explain how they go together.”
 

Longitudinal study 25 years before and 25 years after type 2 diagnosis

Dr. Heald presented the findings at a session on inflammation in diabetes at the annual meeting of the European Association for the Study of Diabetes. The work was also published in Diabetes Therapy.

The researchers wanted to investigate the pattern of comorbidities in the years and decades prior to a diagnosis of type 2 diabetes as well as after: “With the database we used, called DARE [Diabetes Alliance for Research in England], we are able to explore phenomena longitudinally going right back to the beginning of their digital health records, looking at phenotypes over time.”

By mapping significant health issues in people who went on to develop type 2 diabetes alongside those that did not, Dr. Heald managed to develop a continuum spanning 25 years prior and 25 years after diagnosis of type 2 diabetes. The researchers also examined relationships between sociodemographic factors and longitudinal health outcomes of relevance to cardiac conditions and lower respiratory tract infections. His talk in Hamburg primarily addressed clinical phenotypes before the point of diagnosis.

Data were drawn from 1,932 people with (1,196) and without (736) type 2 diabetes. Participants in both groups were aged 66-67 years, 43%-46% were women, age at diagnosis was 50-52 years, and participants lived in Greater Manchester, United Kingdom.

In the years leading up to type 2 diagnosis, individuals consistently exhibited a considerable increase in several clinical phenotypes, reported Dr. Heald. Of note, he added, “immediately prior to type 2 diagnosis, there was a significantly greater proportion of hypertension at 35%, respiratory tract infection at 34%, heart disease at 17%, ear, nose, and throat infection at 19%, and asthma at 12%. And by comparison, the corresponding disease trajectory in matched controls was much less dramatic.”

“There is a huge difference in people who went on to receive a diagnosis of type 2 diabetes and those who did not, and not just what we’d expect – so hypertension for example or manifestations of renal disease, but importantly inflammatory disorders are more common,” he emphasized.

In addition, a larger signal for ischemic heart disease was seen just before type 2 diabetes diagnosis.

These data suggest that longitudinal clinical histories prior to a diagnosis of type 2 diabetes might offer new information, both genetic and nongenetic, about development of type 2 diabetes in relation to comorbidities.

After type 2 diabetes diagnosis, the proportion of people exhibiting coronary artery disease, hypertension, chronic kidney disease, retinopathy, and infections climbed rapidly before plateauing, reported Dr. Heald. “We also know that individuals with coronary artery disease are more highly represented in socially disadvantaged groups, and this is borne out in the data at 25 years prior and after type 2 diagnosis.”

Dr. Heald has received speaker fees or contributed to advisory boards from Lilly, AstraZeneca, Janssen, Bristol-Myers Squibb, Besins, Bayer, Sanofi, and Recordati. Research grants from Novo Nordisk, Pfizer, and Besins. Professor Stehouwer has declared no relevant conflicts.

A version of this article first appeared on Medscape.com.

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