Current Therapy - News of Note
Biologics Updates
Dupixent approved in Canada for adults with inadequately controlled COPD
Toronto, ON - Health Canada has approved Dupixent® (dupilumab injection) as an add-on maintenance treatment in adult patients with chronic obstructive pulmonary disease (COPD) characterized by raised blood eosinophils inadequately controlled by the combination of an inhaled corticosteroid (ICS), a long-acting beta2-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), or on a combination of a LABA and a LAMA if ICS is not appropriate. COPD is a respiratory disease that damages the lungs, causes progressive lung function decline and is the fifth leading cause of death in Canada.
This approval was based on findings from two clinical studies conducted in adult patients already receiving maximal standard-of-care inhaled therapy. The BOREAS and NOTUS studies showed a 30% and 34% reduction in moderate or severe exacerbations over one year.
COPD with Type 2 inflammation, characterized by elevated blood eosinophil levels, has limited treatment options — especially for patients who remain uncontrolled despite triple therapy. The approval of Dupixent® covers inadequately controlled patients who are already on a combination of an inhaled corticosteroid (ICS), a long-acting beta2-agonist (LABA) and a long-acting muscarinic antagonist (LAMA), or on a combination of a LABA and a LAMA if ICS is not appropriate.
Dr. Ken Chapman
Director, Asthma & Airway Centre, University Health Network,
Professor of Medicine, University of Toronto
"This is an exciting discovery for some of my most at-risk patients living with COPD. Although we've made slow and steady progress to improve the lives of those who struggle with chronic bronchitis or emphysema, we've had little to offer the most vulnerable of them who have exacerbations frequently. We know that these frequent visits to the walk-in clinic, emergency room or hospital ward mark a period of rapid decline. Research with Dupixent® shows that a simple blood test will identify which of these vulnerable patients is most likely to enjoy fewer flareups, better lung function, and improved quality of life when treated with this novel therapy."
Dr. Jean Bourbeau
Director, COPD clinic and Pulmonary Rehabilitation, McGill University Health Centre (MUHC)
Respirologist, Respiratory Division, Department of Medicine, MUHC
"The unmet need in COPD with acute exacerbations is huge considering not only the patient impact and premature death but COPD being the number one cause of hospital admissions in Canada. Identifying treatable traits of type 2 inflammation and considering a targeted specific therapy strategy in COPD is now possible with a novel biologic therapy such as dupilumab. Let's not accept that it is normal for our patients to continue to have recurrent and/or severe exacerbations, let's take action."
Henry Roberts
Managing Director, Chronic Obstructive Pulmonary Disease Association Canada (COPD Canada)
"Our community members often share how breathlessness forces them into isolation, missing family gatherings and simple pleasures like walking outdoors. The approval of Dupixent® represents a beacon of hope for Canadians living with uncontrolled COPD who have been waiting far too long for meaningful treatment advancements."
James Guy
General Manager Specialty Care and Sanofi Country Lead Canada
"This approval marks a pivotal moment in COPD management for patients in Canada. By advancing breakthrough science in respiratory medicine, we're delivering meaningful solutions for Canadian patients whose condition is not being effectively managed by existing treatments. We are committed to working alongside healthcare providers to ensure this new option reaches patients living with uncontrolled COPD."
About BOREAS and NOTUS Phase 3 Trials
The approval is based on results from the landmark phase 3 BOREAS and NOTUS studies, which were separately published in The New England Journal of Medicine and evaluated the efficacy and safety of Dupixent® in adults with uncontrolled COPD with evidence of type 2 inflammation (i.e., blood eosinophils ≥300 cells per μL). All patients were on background maximal standard-of-care inhaled therapy (with nearly all on triple therapy). In terms of efficacy, Dupixent® patients in BOREAS (n=468) and NOTUS (n=470) experienced the following, respectively, compared to placebo (BOREAS n=471; NOTUS n=465):
30% and 34% reduction in the annualized rate of moderate or severe COPD exacerbations over 52 weeks, the primary endpoint.
Improvements in lung function (pre-bronchodilator FEV1) from baseline by 160 mL and 139 mL at 12 weeks compared to 77 mL and 57 mL. These improvements were observed as early as week 2 and 4 and were sustained at 52 weeks in both studies.
Improvements in health-related quality of life (statistically significant in BOREAS and nominally significant in NOTUS), as assessed by the St. George's Respiratory Questionnaire.
Safety results in both studies were generally consistent with the known safety profile of Dupixent® in its approved indications. The most common side effects across indications include injection site reactions, conjunctivitis, conjunctivitis allergic, arthralgia, oral herpes, and eosinophilia. Adverse events more commonly observed with Dupixent® (≥5%) compared to placebo in either COPD study were back pain, COVID-19, diarrhea, headache and nasopharyngitis. Additional adverse reactions of injection site bruising, injection site induration, injection site rash and injection site dermatitis were reported in the COPD studies.
Dupixent® for COPD patients have been approved by other regulatory authorities around the world including the European Union, the US, China and Japan.
For more information: https://tinyurl.com/5x4erx2e
Pooled analysis reveals lower risk for severe exacerbations with dupilumab in COPD
Amsterdam, the Netherlands - Receiving dupilumab for 52 weeks lowered the risk for severe exacerbations vs. placebo in adults with COPD and type 2 inflammation, according to pooled trial data presented at the European Respiratory Society International Congress. “Severe exacerbations are associated with substantial short-term and long-term consequences, including significant loss of lung function and, in many cases, death,” Surya P. Bhatt, MD, professor in the division of pulmonary, allergy and critical care medicine at The University of Alabama at Birmingham, told Healio. “Preventing these events can significantly impact the life course of disease in these patients,” Bhatt said. In a post hoc analysis of pooled BOREAS and NOTUS phase 3 trial data, Bhatt and colleagues evaluated adults with COPD and type 2 inflammation (blood eosinophil count 300 cells/μL at screening) on long-acting beta agonists/long-acting muscarinic antagonist/inhaled corticosteroid who received either 300 mg subcutaneous dupilumab (Dupixent; Regeneron, Sanofi; n = 938) or placebo (n = 936) every 2 weeks to determine how the drug impacts risk for severe exacerbations, ED visit rates and systemic corticosteroid use. Notably, the FDA approved dupilumab for treating adults with poorly controlled COPD with type 2 inflammation about 1 year ago. As previously reported, 300 mg dupilumab every 2 weeks for 52 weeks showed a decrease in the annualized moderate/severe exacerbation rate, a positive change in prebronchodilator FEV1 and safety in adults with moderate to severe COPD and type 2 inflammation at week 52 in a pooled analysis of BOREAS and NOTUS. Receiving dupilumab for 52 weeks also led to health-related quality of life improvement in the pooled population, and the benefits seen with dupilumab did not change based on investigator-reported emphysema.
For more information: https://tinyurl.com/jfbyn6dr
Dupilumab benefits patients with COPD, type 2 inflammation regardless of emphysema
SAN FRANCISCO, CA — Among patients with COPD and type 2 inflammation, investigator-reported emphysema did not change benefits seen with dupilumab, according to research presented at the American Thoracic Society International Conference. “In the BOREAS and NOTUS trials, one of the inclusion criteria was the presence of cough and expectoration for 3 months in the previous year,” Surya P. Bhatt, MD, professor in the division of pulmonary, allergy and critical care medicine at The University of Alabama at Birmingham, told Healio. “The findings of this study indicate that the benefits of dupilumab in patients with COPD and type 2 inflammation are not confined to those with predominant airway disease but are also applicable to those with emphysema,” Bhatt said. In this post hoc analysis of pooled BOREAS and NOTUS phase 3 trial data, Bhatt and colleagues assessed 1,874 adults with moderate to severe COPD and type 2 inflammation (blood eosinophil count ≥ 300 cells/μL) who were current or former smokers to determine if investigator-reported emphysema impacts benefits observed with dupilumab (Dupixent; Sanofi, Regeneron) in exacerbation rate and lung function. As Healio previously reported, 300 mg dupilumab every 2 weeks for 52 weeks showed a decrease in the annualized moderate/severe exacerbation rate, a positive change in prebronchodilator FEV1 and safety in adults with moderate to severe COPD and type 2 inflammation at week 52 in a pooled analysis of BOREAS and NOTUS. Notably, receiving dupilumab for 52 weeks also led to health-related quality of life improvement in the pooled population. Researchers reported emphysema in 590 patients (31.5%), of which 289 received dupilumab and 301 received placebo. In both those with and without investigator-reported emphysema, the rate of annualized moderate/severe exacerbations dropped to a similar degree with dupilumab vs. placebo (with emphysema, relative risk [RR] = 0.66; 95% CI, 0.53-0.82; without emphysema, RR = 0.7; 95% CI, 0.58-0.85), according to the analysis. Between baseline and week 12, researchers additionally found a comparable level of improvement in prebronchodilator FEV1 with dupilumab vs. placebo when split into those with emphysema (least-squares mean difference, 83 mL; 95% CI, 35-131) and those without emphysema (least-squares mean difference, 83 mL; 95% CI, 45-120).Researchers noted that there was no significant difference in either outcome between the group with emphysema and the group without emphysema, that dupilumab was beneficial regardless of whether the patient had investigator-reported emphysema. “These findings are reassuring in that future studies of biologics targeting airway inflammation do not need to exclude individuals with emphysema,” Bhattsaid.
For more information: https://tinyurl.com/38nabawp
Dupilumab helps patients with COPD, type 2 inflammation avoid negative outcomes
SAN FRANCISCO, CA — The likelihood for avoidance of five clinically important outcomes in patients with COPD and type 2 inflammation was greater with dupilumab vs. placebo, according to findings from a win ratio analysis. “Dupilumab is already approved for eligible patients with uncontrolled COPD, but these data provide further granularity on the potential impact,” said Sanjay Ramakrishnan, PhD, MBBS, FRACP, senior lecturer at The University of Western Australia and research group leader at the Institute for Respiratory Health. These data on dupilumab (Dupixent; Sanofi, Regeneron) were presented at the American Thoracic Society International Conference. “When compared to placebo, patients on dupilumab had a decreased likelihood of a composite of events including death, hospitalization, worsening symptoms and lung function decline. “Physicians can now clearly explain to patients the ways in which they stand to benefit with adding dupilumab into their COPD management plan: running the COPD race with dupilumab means you are 31% more likely to avoid a combination of potentially debilitating outcomes,” Ramakrishnan said.In this win ratio analysis, Ramakrishnan and colleagues assessed adults with moderate to severe COPD and type 2 inflammation (blood eosinophil count ≥ 300 cells/μL) receiving triple therapy from the BOREAS and NOTUS phase 3 trials to find out the difference in clinically important endpoints at 52 weeks between patients receiving 300 mg dupilumab every 2 weeks (n = 938) and patients receiving placebo (n = 936). Notably, a win ratio analysis is “a simple way to appreciate the benefit of [a] treatment” using the most clinically important outcomes, Ramakrishnan told Healio. “Assessing multiple endpoints simultaneously in clinical trials can be challenging because not all outcomes have equivalent clinical importance,” Ramakrishnan said. “A win ratio analysis provides a way to evaluate key outcomes in tandem, but also ranks them in order of clinical importance, allowing for a more complete and appropriate comparison of multiple endpoints between dupilumab and placebo.” The most clinically important outcome in this patient population was “avoiding hospital,” according to the analysis. Researchers also identified moderate exacerbations, lung function loss and symptom deterioration as clinically important outcomes. All four factors plus death made up one outcome. “The approach creates a single measurement that provides a more accurate reflection of treatment efficacy that takes into account the impact of different clinical outcomes on a patient’s life,” Ramakrishnan said. All incorporated into one outcome, researchers reported that the likelihood for avoidance of death, hospitalization, exacerbations, worsening symptoms and worsening lung function was 31% greater (win ratio, 1.31; 95% CI, 1.15-1.48) in the dupilumab vs. placebo group. “Patients receiving dupilumab are 31% more likely than placebo to ‘win’ on a combination of important outcomes,” Ramakrishnan said. Dupilumab continued to be favored over placebo when broken down into the individual clinically important outcomes, according to the analysis. Researchers highlighted that dupilumab had more wins — achievement of the more desirable outcome — vs. losses than placebo for death or a hospital admission/ED visit lasting 24 hours or longer (7.6% vs. 5.6%), moderate exacerbation or ED visit lasting less than 24 hours (22.1% vs. 17.9%) and total number of moderate or severe exacerbations during the evaluated 52 weeks (3.8% vs. 2.8%). “What was quite striking was every 16th patient treated with dupilumab stopped having exacerbations completely,” Ramakrishnan said. “This is incredible, considering participants were having an average of two exacerbations in the previous year.” Dupilumab also had more wins vs. losses for percent-predicted post-bronchodilator FEV1 worsening of at least 100 mL at week 52 compared with placebo (12.1% vs. 8.2%), according to the analysis. Lastly, improvement in St. George’s Respiratory Questionnaire or Respiratory Symptom Tool for COPD scores was won more than lost by dupilumab vs. placebo (2% vs. 1.5%). “We are pleased that the results were in line with what we would have expected based on the pivotal phase 3 trials for dupilumab in COPD, underscoring how it improves multiple, clinically important signs and symptoms of disease compared to placebo,” Ramakrishnan said. Looking ahead, Ramakrishnan said this analysis may have an impact on future trials in patients with COPD. “These data could inform novel ways of conducting clinical trials in COPD to researchers and funders, by demonstrating a robust unified approach to simultaneously rank and assess outcomes of clinical importance to patients,” Ramakrishnan said.
For more information: https://tinyurl.com/2rk3938e
Dupilumab Improves Quality of Life for COPD Patients
BOSTON, MA - Patients with chronic obstructive pulmonary disease (COPD) and type 2 inflammation had greater improvements in quality of life with dupilumab (Dupixent) versus placebo, according to a pooled analysis of data from the phase III BOREAS and NOTUS trials. At 52 weeks, the least-squares mean difference from baseline in the total St. George's Respiratory Questionnaire (SGRQ) score with dupilumab versus placebo was -3.4 points (95% CI -5.0 to -1.8, nominal P<0.0001), reported Surya Bhatt, MD, of the University of Alabama at Birmingham, during the CHEST annual meeting hosted by the American College of Chest Physicians. For individual SGRQ domain scores, the least-squares mean differences at 52 weeks with dupilumab versus placebo were: Symptoms: -3.5 (95% CI -5.5 to -1.5, nominal P<0.0006) Impacts: -2.9 (95% CI -4.6 to -1.1, nominal P=0.0012) Activity: -4.0 (95% CI -5.9 to -2.1, nominal P<0.0001) Impairments in quality of life "contribute significantly to morbidity in COPD," Bhatt told attendees. "The total SGRQ score changed quickly," he noted. "Within 4 weeks there was a big difference between the placebo arm and the [dupilumab] arm, and this difference persisted over the 52-week time period." "Even in the subdomains, this trend was very similar," he added. "Dupilumab has a significant impact on quality of life in addition to its primary impact on exacerbation reduction and secondary reduction improvements in lung function" in patients with COPD. The 36-item SGRQ measures patient-reported impacts of obstructive airway diseases on overall health, common daily activities, and perceived well-being. The total SGRQ score and those of three domains range from 0 to 100, with higher scores indicating poorer health-related quality of life. At baseline, the total SGRQ score "was quite high, to the tune of almost 50 on average in both groups," Bhatt pointed out. For the specific domains across both groups, the mean activity score was approximately 66, the symptoms domain score was roughly 59, and the impacts domain score was about 38. "Although dupilumab appears to be a promising biologic treatment for COPD, its use is currently limited to those with an eosinophilic phenotype, which represents a minority of patients with the disease," session moderator Subhakar Kandi, MBBS, MD, of Kamineni Hospitals in Hyderabad, India, told MedPage Today. More treatments are desperately needed for COPD because of its substantial burden on patients and caregivers, he emphasized. However, he noted that he would have liked to see data from the analysis broken down according to disease severity or exacerbation risk. Dupilumab, an injectable interleukin (IL)-4 and IL-13 pathway inhibitor, recently received FDA approval as the first-ever biologic for treatment of COPD. It is indicated as an add-on maintenance treatment for inadequately controlled COPD with an eosinophilic phenotype. Primary support for the approval came from the phase III BOREAS trial, showing that dupilumab led to a 30% reduction in annual exacerbations, and from the phase III NOTUS trial, which showed a 34% reduction. The BOREAS and NOTUS trials assessed the efficacy and safety of dupilumab as add-on therapy in patients with COPD and type 2 inflammation (blood eosinophil count ≥300 cells/µL) who had moderate-to-severe airflow limitation and were taking inhaled triple therapy. This prespecified pooled analysis assessed the change from baseline in the SGRQ total and domain scores at week 52 in patients enrolled in those trials. The final population in this analysis included 830 patients in the dupilumab group (mean age 65, 65.9% men) and 830 in the placebo group (mean age 65, 67.6% men). Most patients were former smokers (70-71%).
For more information: https://tinyurl.com/2vedt6v5