Efficacy and safety of rademikibart (CBP-201), a next-generation mAb targeting IL-4Rα, in adults with moderate to severe atopic dermatitis: A phase 2 randomized trial (CBP-201-WW001).

BACKGROUND: Rademikibart (CBP-201) is a next-generation IL-4 receptor alpha-targeting antibody. OBJECTIVE: We sought to evaluate rademikibart in adults with moderate to severe atopic dermatitis. METHODS: A total of 226 patients were randomized, double-blind, to subcutaneous rademikibart (300 mg every 2 weeks [Q2W], 150 mg Q2W, 300 mg every 4 weeks [Q4W]; plus 600-mg loading dose) or placebo. Randomization began in July 2020. The trial was completed in October 2021. RESULTS: The WW001 phase 2 trial achieved its primary end point: significant percent reduction from baseline in least-squares mean Eczema Area Severity Index (EASI) to week 16 with rademikibart 300 mg Q2W (-63.0%; P = .0007), 150 mg Q2W (-57.6%; P = .0067), 300 mg Q4W (-63.5%; P = .0004) versus placebo (-39.7%). EASI scores decreased significantly with 300 mg Q2W and Q4W at the earliest assessment (week 2), with no evidence of plateauing by week 16. Significant improvements were also observed in secondary end points, including pruritus. Across the primary and secondary end points, efficacy tended to be comparable with 300 mg Q2W and Q4W dosing. Rademikibart and placebo had similar, low incidence of treatment-emergent adverse events (TEAEs) (48% vs 54%), serious TEAEs (1.8% vs 3.6%), TEAEs leading to treatment discontinuation (1.2% vs 1.8%), conjunctivitis of unspecified cause (2.9% vs 0%), herpes (0.6% vs 1.8%), and injection-site reactions (1.8% vs 1.8%). Although no discontinuations were attributed to coronavirus disease 2019, pandemic-related restrictions likely had an impact on trial conduct. CONCLUSIONS: Rademikibart was efficacious and well tolerated at Q2W and Q4W intervals. Q4W dosing is a more convenient frequency than approved for current therapies.

Clinical Bioequivalence of OT329 SOLIS and ADVAIR DISKUS in Adults with Asthma.

RATIONALE: OT329 SOLIS is a generic candidate for the branded asthma treatment, ADVAIR DISKUS (fluticasone propionate/salmeterol xinafoate), and, as such, the manufacturer is required to provide evidence of clinical "bioequivalence" as a condition for regulatory approval. OBJECTIVES: The objective of the current study was to determine if SOLIS and DISKUS provided bioequivalent improvements in lung function at two time points: Day 1 and Week 4. METHODS: This study was a randomized, multiple-dose, placebo-controlled, parallel-group design conducted in the United States (NCT02260492) with a 2-week run-in followed by a 4-week treatment period. Consenting patients were randomized to treatment with OT329 SOLIS 100/50, ADVAIR DISKUS 100/50, or placebo. Lung function was measured predose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours after the first dose to test equivalence of the ß-agonist salmeterol component based on FEV1 area under the curve (0-12 h). After 4 weeks of twice-daily dosing, trough (predose) FEV1 was measured to evaluate equivalence of the fluticasone propionate corticosteroid component. Bioequivalence was concluded if the 90% confidence interval (CI) for the ratio of the products fell within 80-125%. MEASUREMENTS AND MAIN RESULTS: Of the 1,524 screened, 879 patients with asthma were randomized to treatment (n = 418 SOLIS, 419 DISKUS, 42 placebo). OT329 SOLIS and ADVAIR DISKUS were bioequivalent at Day 1, with an FEV1 area under the curve (0-12 h) test/reference ratio of 108% (90% CI = 94-122%). Likewise, the products were bioequivalent at Week 4 with a trough FEV1 test/reference ratio of 105% (90% CI = 90-119). Both active treatments were superior to placebo (P < 0.05) at both time points. CONCLUSIONS: The data support a conclusion of clinical bioequivalence of OT329 SOLIS to ADVAIR DISKUS. Clinical trial registered with www.clinicaltrials.gov (NCT02260492).

Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies.

BACKGROUND: Increases in T helper (Th) 2 cytokine concentrations have been seen in atopic asthma, with interleukin 4 and interleukin 13 thought to have a role in the physiological response to allergen challenge. Our aim was to assess the therapeutic effect of pitrakinra, an interleukin-4 variant that targets allergic Th2 inflammation by potently inhibiting the binding of interleukin 4 and interleukin 13 to interleukin-4Ralpha receptor complexes. METHODS: In two independent randomised, double-blind, placebo-controlled, parallel group phase 2a clinical trials, patients with atopic asthma were treated with pitrakinra or placebo via two routes. In study 1, patients were randomly assigned to receive either 25 mg pitrakinra (n=12) or placebo (n=12) by subcutaneous injection once daily. In study 2, patients were randomly assigned to receive either 60 mg pitrakinra (n=16) or placebo (n=16) by nebulisation twice daily. Inhaled allergen challenge was done before and after 4 weeks of treatment. The primary endpoint for study 1 was maximum percentage decrease in forced expiratory volume in 1 s (FEV1) over 4-10 h after allergen challenge, whereas that in study 2 was average percentage decrease in FEV(1) over 4-10 h after allergen challenge. All patients except those with baseline data only were included in our analyses. These trials are registered with ClinicalTrials.gov, numbers NCT00535028 and NCT00535031. FINDINGS: No patients dropped out or were lost to follow-up in study 1; in study 2, two patients in the placebo group and one in the pitrakinra group dropped out or were lost to follow-up. These individuals had baseline data only, and were excluded from the analyses. In study 1, there was a 17.1% maximum percentage decrease in FEV1 in the pitrakinra group; by contrast, the maximum decrease was 23.1% in the placebo group (difference 6%, 95% CI -4.37 to 16.32; p=0.243). In study 2, there was a 4.4% average percentage decrease in FEV1 in the pitrakinra group; by contrast, the average percentage decrease was 15.9% in the placebo group (3.7 [95% CI 2.08-6.25] times lower in the pitrakinra group; p=0.0001). There were fewer asthma-related adverse events (p=0.069) and fewer adverse events requiring beta-agonist rescue (p=0.031) after subcutaneous administration of pitrakinra than with placebo. There were too few asthma-related adverse events in study 2 to assess the effect of inhalation of pitrakinra on adverse events. INTERPRETATION: Local treatment, targeted at inhibition of interleukins 4 and 13 in the lung, could substantially diminish the symptoms of asthma.

Neutrophil elastase induces mucus cell metaplasia in mouse lung.

Goblet cell hyperplasia in the superficial airway epithelia is a signature pathological feature of chronic bronchitis and cystic fibrosis. In these chronic inflammatory airway diseases, neutrophil elastase (NE) is found in high concentrations in the epithelial lining fluid. NE has been reported to trigger mucin secretion and increase mucin gene expression in vitro. We hypothesized that chronic NE exposure to murine airways in vivo would induce goblet cell metaplasia. Human NE (50 microg) or PBS saline was aspirated intratracheally by male Balb/c (6 wk of age) mice on days 1, 4, and 7. On days 8, 11, and 14, lung tissues for histology and bronchoalveolar lavage (BAL) samples for cell counts and cytokine levels were obtained. NE induced Muc5ac mRNA and protein expression and goblet cell metaplasia on days 8, 11, and 14. These cellular changes were the result of proteolytic activity, since the addition of an elastase inhibitor, methoxysuccinyl Ala-Ala-Pro-Val chloromethylketone (AAPV-CMK), blocked NE-induced Muc5ac expression and goblet cell metaplasia. NE significantly increased keratinocyte-derived chemokine and IL-5 in BAL and increased lung tissue inflammation and BAL leukocyte counts. The addition of AAPV-CMK reduced these measures of inflammation to control levels. These experiments suggest that NE proteolytic activity initiates an inflammatory process leading to goblet cell metaplasia.

Keratinocyte growth factor and the transcription factors C/EBP alpha, C/EBP delta, and SREBP-1c regulate fatty acid synthesis in alveolar type II cells.

Strategies to stimulate endogenous surfactant production require a detailed understanding of the regulation of lipogenesis in alveolar type II cells. We developed culture conditions in which keratinocyte growth factor (KGF) stimulates fatty acid and phospholipid synthesis. KGF stimulated acetate incorporation into phosphatidylcholine, disaturated phosphatidylcholine, and phosphatidylglycerol more than 5% rat serum alone. To determine the mRNA levels of lipogenic enzymes and transport proteins, we analyzed gene expression by oligonucleotide microarrays. KGF increased the mRNA levels for fatty acid synthase, stearoyl-CoA desaturase-1 (SCD-1), and epidermal fatty acid-binding protein more than rat serum alone. In addition, KGF increased the mRNA levels of the transcription factors CCAAT/enhancer-binding protein alpha (C/EBPalpha) and C/EBPdelta as well as SREBP-1c (ADD-1), but not PPARgamma. These changes in C/EBPalpha and C/EBPdelta were confirmed by in situ hybridization. SCD-1 was also found to be highly expressed in alveolar type II cells in vivo. Furthermore, KGF increased protein levels of fatty acid synthase, C/EBPalpha, C/EBPdelta, SREBP-1, epidermal fatty acid-binding protein, and SCD. Finally, the liver X receptor agonist T0901317 increased acetate incorporation and SREBP-1 but not SREBP-2 protein levels. In summary, KGF stimulates lipogenesis in type II cells by a coordinated expression of lipogenic enzymes and transport proteins regulated by C/EBP isoforms and SREBP-1c.

A murine model of cigarette smoke-induced pulmonary inflammation using intranasally administered smoke-conditioned medium.

To date, few animal models of chronic obstructive pulmonary disease (COPD) exist that are ideal for the evaluation of pathophysiology, as they typically require many months of cigarette smoke exposure in inhalation facilities. Here we show that pulmonary inflammation and some of the inflammatory hallmarks of COPD can be induced in mice by cigarette smoke-conditioned media (CS) administered by the intranasal route. Balb/c mice were challenged with CS for up to 40 days. At the end of smoke treatment, mice were sacrificed and bronchoalveolar lavage (BAL) fluid collected. Total cell counts and cell differentials were performed. Enzyme-linked immunosorbent assays (ELISAs) for KC and tumor necrosis factor alpha (TNF-alpha) were performed on BAL fluid. Lungs and nasal cavities were examined histologically. Intranasal CS treatment significantly increased BAL neutrophils, lymphocytes, KC, TNF-alpha, and mucin. Changes in pulmonary reactivity to methacholine were also observed in mice challenged with CS for 40 days. The model described above demonstrates that within 1 to 8 weeks of intranasal instillation of CS, mice develop pulmonary inflammation and cellular lung changes that are characteristic of human COPD and therefore may be a good short-term in vivo model that can be utilized to monitor intervention strategies targeted for COPD.