Safety and Efficacy of Lebrikizumab in Adolescent Patients with Moderate-to-Severe Atopic Dermatitis: A 52-Week, Open-Label, Phase 3 Study.

INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disorder with limited treatment options for adolescents with moderate-to-severe disease. Lebrikizumab, a monoclonal antibody targeting interleukin (IL)-13, demonstrated clinical benefit in previous Phase 3 trials: ADvocate1 (NCT04146363), ADvocate2 (NCT04178967), and ADhere (NCT04250337). We report 52-week safety and efficacy outcomes from ADore (NCT04250350), a Phase 3, open-label study of lebrikizumab in adolescent patients with moderate-to-severe AD. The primary endpoint was to describe the proportion of patients who discontinued from study treatment because of adverse events (AEs) through the last treatment visit. METHODS: Adolescent patients (N = 206) (≥ 12 to < 18 years old, weighing ≥ 40 kg) with moderate-to-severe AD received subcutaneous lebrikizumab 500 mg loading doses at baseline and Week 2, followed by 250 mg every 2 weeks (Q2W) thereafter. Safety was monitored using reported AEs, AEs leading to treatment discontinuation, vital signs, growth assessments, and laboratory testing. Efficacy analyses included Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA), Body Surface Area (BSA), (Children's) Dermatology Life Quality Index ((C)DLQI), and Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety, and PROMIS Depression. RESULTS: 172 patients completed the treatment period. Low frequencies of SAEs (n = 5, 2.4%) and AEs leading to treatment discontinuation (n = 5, 2.4%) were reported. Overall, 134 patients (65%) reported at least one treatment-emergent AE (TEAE), most being mild or moderate in severity. In total, 62.6% achieved IGA (0,1) with ≥ 2-point improvement from baseline and 81.9% achieved EASI-75 by Week 52. The EASI mean percentage improvement from baseline to Week 52 was 86.0%. Mean BSA at baseline was 45.4%, decreasing to 8.4% by Week 52. Improvements in mean change from baseline (CFB) to Week 52 were observed in DLQI (baseline 12.3; CFB - 8.9), CDLQI (baseline 10.1; CFB - 6.5), PROMIS Anxiety (baseline 51.5; CFB - 6.3), and PROMIS Depression (baseline 49.3; CFB - 3.4) scores. CONCLUSIONS: Lebrikizumab 250 mg Q2W had a safety profile consistent with previous trials and significantly improved AD symptoms and quality of life, with meaningful responses at Week 16 increasing by Week 52. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04250350.

Atopic dermatitis is a chronic relapsing inflammatory skin disease that affects up to 15% of adolescents worldwide, with up to 50% suffering from moderate-to-severe disease. Signs and symptoms include dry, cracked skin; redness; itching; and painful lesions, which can negatively affect quality of life and lead to complications, including skin infections. Adolescents also report increased rates of anxiety and stress. Lebrikizumab is a novel monoclonal antibody that binds with high affinity and slow off-rate to interleukin (IL)-13, the key cytokine in atopic dermatitis, blocking the downstream effects of IL-13 with high potency. Lebrikizumab has been shown previously to improve symptoms of atopic dermatitis, including itch, skin clearance, and quality of life in ADvocate1, ADvocate2 and ADhere. The ADore study aimed to evaluate the safety and efficacy of lebrikizumab in adolescents with moderate-to-severe atopic dermatitis. Investigators recruited patients ≥ 12 to < 18 years old, weighing ≥ 40 kg, from Australia, Canada, Poland, and the US who were diagnosed with moderate-to-severe atopic dermatitis. These patients received a loading dose of 500 mg of lebrikizumab at Weeks 0 and 2, followed by 250 mg every 2 weeks for 52 weeks. The safety profile of lebrikizumab was consistent with previously published reports, with mostly mild or moderate adverse events, which did not lead to treatment discontinuation. Lebrikizumab improved skin clearance; 62.6% of patients had clear or almost clear skin by the end of the trial. Lebrikizumab also improved the patients' quality of life. These safety and efficacy results support lebrikizumab's role in treating adolescents with moderate-to-severe atopic dermatitis. Safety and Efficacy of Lebrikizumab in Adolescent Patients with Moderate-to-Severe Atopic Dermatitis: A 52-Week, Open-Label, Phase 3 Study (MP4 44681 KB).

Baricitinib and primary biliary cholangitis.

BACKGROUND AND AIMS: There is an unmet need for alternative treatments for patients with primary biliary cholangitis (PBC) who do not respond to treatment with ursodeoxycholic acid (UDCA). A proof-of-concept study of baricitinib, an orally administered Janus kinase 1 and 2 inhibitor, was initiated to evaluate its use in PBC patients. APPROACH AND RESULTS: Patients with PBC showing inadequate response or intolerance to UDCA were eligible. This was a randomized, double-blinded placebo-controlled trial. Enrollees were assigned 1:1 to baricitinib (2 mg/day) or placebo. Endpoints included change in alkaline phosphatase (ALP), itch Numeric Rating Score (NRS), and fatigue NRS at 12 weeks post-baseline; exploratory markers included high sensitivity C-reactive protein (hs-CRP) and Enhanced Liver Fibrosis (ELF) score.Due to low enrollment, the study was terminated early. Two patients were enrolled and completed the trial; 1 was randomized to receive baricitinib and 1 to placebo. Over the treatment period, the baricitinib-treated patient demonstrated a 30% decrease in ALP and a 7-point improvement in the itch NRS, but a 2-point increase in the Fatigue NRS. Markers of inflammation and liver fibrosis (hs-CRP and ELF score) also improved over the study period. In contrast, the placebo-treated patient showed no improvement in primary or secondary endpoints. A single non-serious treatment-emergent adverse event of moderate sinusitis was reported by the baricitinib-treated patient at day 47. CONCLUSIONS: In a 12-week trial, a patient with PBC showing inadequate response to treatment with UDCA demonstrated a dramatic response to treatment with baricitinib.

Dose reduction of baricitinib in patients with rheumatoid arthritis achieving sustained disease control: results of a prospective study.

OBJECTIVES: This study investigated the effects of dose step-down in patients with rheumatoid arthritis (RA) who achieved sustained disease control with baricitinib 4 mg once a day. METHODS: Patients who completed a baricitinib phase 3 study could enter a long-term extension (LTE). In the LTE, patients who received baricitinib 4 mg for ≥15 months and maintained CDAI low disease activity (LDA) or remission (REM) were blindly randomised to continue 4 mg or taper to 2 mg. Patients could rescue (to 4 mg) if needed. Efficacy and safety were assessed through 48 weeks. RESULTS: Patients in both groups maintained LDA (80% 4 mg; 67% 2 mg) or REM (40% 4 mg; 33% 2 mg) over 48 weeks. However, dose reduction resulted in small, statistically significant increases in disease activity at 12, 24 and 48 weeks. Dose reduction also produced earlier and more frequent relapse (loss of step-down criteria) over 48 weeks compared with 4 mg maintenance (23% 4 mg vs 37% 2 mg, p=0.001). Rescue rates were 10% for baricitinib 4 mg and 18% for baricitinib 2 mg. Dose reduction was associated with a numerically lower rate of non-serious infections (30.6 for baricitinib 4 mg vs 24.9 for 2 mg). Rates of serious adverse events and adverse events leading to discontinuation were similar across groups. CONCLUSIONS: In a large randomised, blinded phase 3 study, maintenance of RA control following induction of sustained LDA/REM with baricitinib 4 mg was greater with continued 4 mg than after taper to 2 mg. Nonetheless, most patients tapered to 2 mg could maintain LDA/REM or recapture with return to 4 mg if needed.

Association between EGF +61A/G polymorphism and gastric cancer in Caucasians.

AIM: To investigate the association between epidermal growth factor (EGF) +61A/G polymorphism and susceptibility to gastric cancer, through a cross-sectional study. METHODS: Polymerase chain reaction restriction fragment length polymorphism analyses were used to genotype EGF +61 in 207 patients with gastric lesions (162 patients with gastric adenocarcinomas, 45 with atrophy or intestinal metaplasia) and 984 controls. All subjects were Caucasian. RESULTS: Genotype distribution was 23.5% for GG and 76.5% for GA/AA in the control group, 18.4% for GG and 68.6% for GA/AA in the entire group with gastric lesions and 17.9% for GG and 82.1% for GA/AA in the group with gastric adenocarcinoma. No statistically significant associations were found between EGF +61 variants and risk for developing gastric cancer [odds ratios (OR) = 1.41, 95% confidence intervals (CI): 0.90-2.21, P = 0.116]. However, the stratification of individuals by gender revealed that males carrying A alleles (EGF +61A/G or AA) had an increased risk for developing gastric cancer as compared to GG homozygous males (OR = 1.55, 95% CI: 1.05-2.28, P = 0.021). CONCLUSION: In summary, we found that males who were A carriers for EGF +61 had an increased risk for developing gastric cancer. This result may be explained by the suggestion that women secrete less gastric acid than men.

Epstein-Barr virus in healthy individuals from Portugal.

INTRODUCTION: The Epstein-Barr virus (EBV) persists for long periods in latent state inside B-lymphocytes after primary infections, and reactivation usually occurs associated to immunosuppression conditions of the host. Recently, the detection of EBV DNA in circulation has been suggested as a predictor marker for the development of EBV related malignancies. AIM OF THE STUDY: The aim of our study was to characterize the frequency of circulating EBV in healthy individuals (n=508) from the North region of Portugal, using peripheral blood samples. Detection was performed by Nested-PCR which amplifies a fragment from the BamHIW region of the EBV genome. RESULTS: Our results revealed an overall frequency of 37.2% positive cases for EBV in circulation, with distinct distribution according to genre (39.7% in male individuals and 33.2% in females). We also found that EBV is more frequent in individuals with more than 56 years old compared to individuals with less than 56 years old (p=0.032; RR=1.41), mainly in the male group (p=0.024; OR=1.51). CONCLUSION: This is the first study which characterizes the frequency of EBV in circulation in healthy donors from the Northern Region of Portugal, revealing increased frequency of EBV in circulation in healthy individuals with differences depending on gender or age. Further studies are required to analyze the role of circulating EBV in the definition of susceptibilities to EBV associated diseases.

Epstein-Barr virus is associated with gastric carcinoma: the question is what is the significance?

AIM: To examine the possible role of the Epstein-Barr Virus (EBV) in the development of gastric adenocarcinoma (GC). It is unclear whether EBV is involved in GC development or is a consequence of gastric inflammation secondary to immunosuppressive treatments. METHODS: A systematic review was carried out of all published observational studies on the temporal association between EBV and GC, with a view to determine a causal relationship. RESULTS: The present study showed that the worldwide crude prevalence of EBV in gastric adenocarcinoma was 8.29%. The prevalence varied from 7.08% for intestinal type and 9.82% for diffuse type of GC. It was observed that Western and Central Asian countries had a significantly higher frequency of EBV positive cases compared to South-Eastern countries. America had the highest EBV-GC prevalence whereas Europe had the lowest. CONCLUSION: The present review has demonstrated a high prevalence of EBV in gastric adenocarcinoma. However, studies designed to assess a temporal relationship and histological association using sensitive techniques should be carried out to establish the role of EBV in GC carcinogenesis.

Overall survival in women with breast cancer: the influence of pepsinogen C gene polymorphism.

We aimed to study the role of an insertion/deletion polymorphism in the Pepsinogen C (PGC) gene in the clinical outcome of 172 breast cancer patients. The six polymorphic alleles were amplified using PCR. Our results indicate that patients carrying the allele 6 present a higher 5-year survival mean (83.4% of 6 allele carriers were alive at 5 years vs. only 68.6% of noncarriers, p=0.001), suggesting a role for this polymorphism in the outcome of breast cancer patients. We hypothesize that PGC polymorphism can be a predictive biomarker in breast cancer, contributing to an individual profile of great interest in clinical oncology.

Gastric cancer in a Caucasian population: role of pepsinogen C genetic variants.

AIM: To study the role of an insertion/deletion polymorphism in the pepsinogen C (PGC) gene, an effective marker for terminal differentiation of the stomach mucosa, in the susceptibility to the development of gastric lesions. METHODS: The study was performed with 99 samples of known gastric lesions and 127 samples without evidence of neoplastic disease. PCR was employed and the 6 polymorphic alleles were amplified: Allele 1 (510 bp), Allele 2 (480 bp), Allele 3/4 (450/460 bp), Allele 5 (400 bp) and Allele 6 (310 bp). RESULTS: Our results revealed that Allele 6 carriers seemed to have protection against the development of any gastric lesion (OR = 0.34; P<0.001), non-dysplastic lesions associated with gastric adenocarcinoma such as atrophy or intestinal metaplasia (OR = 0.28; P<0.001) or invasive GC (OR = 0.39; P = 0.004). CONCLUSION: Our study reveals that the Allele 6 carrier status has a protective role in the development of gastric lesions, probably due to its association with higher expression of PGC. Moreover, the frequency of Allele 6 carriers in the control group is far higher than that obtained in Asian populations, which might represent a genetic gap between Caucasian and Asian populations.