Dupilumab Demonstrates Safety, Efficacy Across Several Type 2 Inflammatory Diseases

Research presented at the European Academy of Allergy and Clinical Immunology (EAACI) Annual Congress demonstrate the safety and efficacy of dupilumab across several progressive diseases with underlying type 2 inflammation, including eosinophilic esophagitis (EoE), severe asthma, and severe chronic rhinosinusitis with nasal polyps (CRSwNP).

Recently approved by the FDA as the first therapy to treat EoE, the indication of dupilumab, a fully human monoclonal antibody that blocks 2 key and central drivers of type 2 inflammation (interleukin [IL]-4 and IL-13), was based on findings of the randomized, double-blind, parallel-group, multicenter, placebo-controlled phase 3 LIBERTY EoE TREET study.

Patients included in Part A and Part B of the 3-part analysis who were given dupulimab 300 mg weekly vs placebo showed significant clinically meaningful improvements in symptomatic and histologic outcomes at week 24, with the drug indicated to be generally well tolerated among these patients. Efficacy was sustained up to week 52 in patients from Part A who continued in Part C, which was an additional study group investigated in the abstract presented today at EAACI.

With dupilumab also approved for the treatment of CRSwNP and asthma, different end points were investigated in abstracts of these diseases during the meeting.

Histological Outcomes and Type 2 Inflammation Transcriptome Signatures in EoE

Presented today, researchers examined the effect of dupilumab on histology and gene expression in patients with EoE from Part A and Part B (week 24) and those from Part A who continued in Part C (week 52) of the phase 3 LIBERTY EoE TREET study.¹

Outcomes assessed included the change from baseline in EoE Histologic Scoring System (HSS) grade and stage scores; the Normalized Enrichment Score (NES) for the EoE Diagnostic Panel (EDP), which included genes associated with remodelling (eg, filaggrin and periostin); and type 2 inflammation gene expression signatures.

Findings showed significant differences for all end points at weeks 24 and 52 of the Part A/B and Part C groups, respectively, who were randomized to dupilumab vs placebo at baseline, as well as those switched from placebo to dupilumab after 24 weeks:

• Least squares mean difference (LSMD) for dupilumab vs placebo in change from baseline to week 24 in HSS grade score was −0.76 (95% CI, −0.91 to −0.61; P < .001) in Part A and –0.68 (95% CI, –0.79 to – 0.57; P < .0001) in Part B
• LSMD for dupilumab vs placebo in change from baseline to week 24 in HSS stage score was −0.74 (95% CI, −0.88 to −0.60; P < .001) in Part A and –0.67 (95% CI, –0.78 to –0.57; P < .0001) in Part B
• LSMD (SD) change from Part A baseline to week 52 in HSS grade score and HHS stage score in Part C were improved for both patients initiated on placebo who switched to dupilumab at week 24 and those on dupilumab for the entire study period (HHS grade score: placebo-dupilumab: LSMD, –0.87 [0.55]; dupilumab/dupilumab: LSMD, –0.87 [0.35]; HHS stage score: placebo-dupilumab: LSMD, –0.87 [0.46]; dupilumab-dupilumab: LSMD, –0.89 [0.28])
• Median difference for dupilumab vs placebo in change from baseline to week 24 in EDP NES was –2.25 (95% CI, –2.72 to –1.73; P < .0001) for Part A and –1.85 (95% CI, –2.44 to –1.15; P < .0001) for Part B
• Median changes from Part A baseline to week 52 in EDP NES in Part C were –2.58 and –2.67 for patients initiated on placebo who switched to dupilumab at week 24 and those on dupilumab for the entire study period, respectively
• Median difference for dupilumab vs placebo in change from baseline to week 24 in type 2 NES was –1.59 (95% CI, –1.74 to –1.27; P < .0001) for Part A and –1.28 (95% CI, –1.82 to –1.07; P < .0001) for Part B.
• Median changes from Part A baseline to week 52 in type 2 NES in Part C were –1.94 and –1.97 for patients initiated on placebo who switched to dupilumab at week 24 and those on dupilumab for the entire study period, respectively

“Dupilumab improved HSS grade and stage total scores and normalized gene expression in patients with EoE at week 24, which was sustained to week 52,” concluded the study authors. “Normalization of transcriptional signatures by dupilumab may be driving improvements in histologic features of EoE.”

Severe Annual Exacerbation Rate and Lung Function in Patients With Severe Asthma

Abstract findings of a post hoc analysis of the Liberty Asthma Quest study were reported yesterday at EAACI.² Prior research from the study shows that add-on dupilumab 200 mg/300 mg every 2 weeks vs placebo significantly reduced severe asthma exacerbations and improved prebronchodilator (BD) forced expiratory volume in 1 second (FEV₁) in patients with uncontrolled, moderate to severe asthma being treated with  medium- or high-dose inhaled corticosteroids (ICS). These effects were found to be greater in patients with the type 2 inflammatory phenotype, fungal sensitization (FS) at baseline.

“Up to 30% of asthma patients show evidence of FS characterized by increased asthma severity, a type 2 response, and potential progression to bronchiectasis/fibrosis,” said the researchers.

A total of 1505 patients at baseline with FS (specific immunoglobulin E [IgE] to fungi [A. alternate, A. fumigatus, C. herbarum] > 0.35 IU/mL) or without FS were assessed for the annualized rate of severe asthma exacerbations (AERs) and change from baseline in pre-BD FEV₁ over the 52-week treatment period.

Of the study cohort at baseline, 282 had FS. Among this group, 155 patients used high-dose ICS (placebo, n = 63; dupilumab, n = 92) and 127 used medium-dose ICS (placebo, n = 45; dupilumab, n = 82). A total of 630 participants did not have FS, with these patients reporting use of either high-dose ICS (placebo, n = 218; dupilumab, n = 412) or medium-dose ICS (placebo, n = 197; dupilumab, n = 396).

Compared with those given placebo, dupilumab treatment was associated with significantly reduced AERs in patients with FS on medium-dose ICS and patients without FS irrespective of ICS dose. A 28% reduction in AERs was seen in patients with FS on high-dose ICS, but this finding did not reach statistical significance.

Moreover, the LSMD from baseline to week 12 in pre-BD FEV₁ for patients treated with dupilumab vs placebo was 0.12 L for FS and high-dose ICS (95% CI, −0.01 to 0.25; P = .0656), 0.15 L for no FS and high-dose ICS (95% CI, 0.08-0.21; P < .0001), 0.13 L for FS and medium-dose ICS (95% CI, −0.01 to 0.28; P = .0721), and 0.18 L for no FS and medium-dose ICS (95% CI, 0.11-0.25; P < .0001) groups.

Symptom-Free Days in Patients With Severe CRSwNP

Another post hoc analysis presented at EAACI on Thursday, June 30, examined the proportion of patients with CRSwNP who achieved symptom-free days (SFDs) in the phase 3 SINUS-24/SINUS-52 studies.³ Prior results of these studies demonstrated improvements in patient-reported daily symptom severity scores in those with CRSwNP receiving dupilumab 300 mg vs placebo every 2 weeks for 24 and 52 weeks, respectively.

“Patients recorded symptom severity for nasal congestion (NC), decreased/loss of smell (LoS), and anterior and posterior rhinorrhea on a scale of 0 to 3 (0 = no symptoms; 3 = severe),” explained the authors. “Proportions of patients with SFDs (score = 0 in the 28-day period before randomization, week 24, and week 52) were compared for dupilumab and placebo. Proportions of patients with SFD were also assessed in the subgroup of patients with prior nasal polpys surgery.”

Of the 723 patients randomized to dupilumab (n = 437) or placebo (n = 286) at baseline, SFDs for either NC, decreased/LoS, anterior rhinorrhea, or posterior rhinorrhea were reported in 4.1% of patients overall during the 28-day period pre-randomization (4.6% and 3.5% in the dupilumab and placebo treatment groups, respectively).

Compared with patients randomized to placebo, those treated with dupilumab were significantly more likely to report SFD for at least 1 symptom in the 28 days before week 24 (35.4% vs 10.8%; odds ratio [OR], 4.92; 95% CI, 3.10-7.82; nominal P < .0001), with this difference further increased in the 28 days before week 52 (50.0% vs 9.2%; OR, 9.10; 95% CI, 4.63-17.88; nominal P < .0001). Significant differences vs placebo (nominal P < .0001) were additionally observed for each symptom individually.

The proportions of patients who reported SFD for at least 1 symptom in the 28 days before week 24 and week 52 of the nasal polyps subgroup were consistent with the overall population.

References

1. Collins MH, Lim WK, Wipperman MF, et al. Dupilumab improves histological outcomes and normalizes disease and type 2 inflammation transcriptome signatures in adult and adolescent patients with eosinophilic oesophagitis: Results from the 3-part phase 3 LIBERTY EoE TREET study. Abstract presented at: 2022 EAACI Annual Congress. Abstract 001140.

2. Corren J, Hanania NA, Busse WW, et al. Severe annual exacerbation rate and lung function in fungal sensitized and fungal not sensitized patients with severe asthma: post hoc analysis of Liberty Asthma Quest study. Abstract presented at: 2022 EAACI Annual Congress. Abstract 001503.

3. Bachert C, Hopkins C, Han JK, et al. Symptom-free days in patients with severe chronic rhinosinusitis with nasal polyps treated with dupilumab. Abstract presented at: 2022 EAACI Annual Congress. Abstract 000372.