East Asian Subgroup Research Articles

Pharmacokinetics and pharmacodynamics of itepekimab in adults with moderate-to-severe atopic dermatitis: Results from two terminated phase II trials.

Interleukin-33 (IL-33) is a proinflammatory alarmin cytokine released by damaged epithelial tissue cells that initiates and amplifies both type 1 and type 2 inflammatory cascades. A role for IL-33 in atopic dermatitis (AD; a chronic, relapsing type 2 inflammatory disease of the skin) has been proposed. Itepekimab is a novel human IgG4P monoclonal antibody against IL-33, currently in clinical development for chronic obstructive pulmonary disease (COPD). Two global phase II studies-a dose-ranging itepekimab monotherapy study (NCT03738423) and a proof-of-concept study of itepekimab alone and in combination with dupilumab (NCT03736967)-were conducted in patients with moderate-to-severe AD to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy; both studies were terminated following an interim analysis of the proof-of-concept study, which failed to demonstrate the efficacy of itepekimab. In these two studies, itepekimab exhibited linear and dose-proportional pharmacokinetics. Pharmacodynamics of total IL-33 indicated that itepekimab saturated binding to the target in serum at 300 mg q2w and q4w doses, and decreased blood eosinophil counts. Concentration-time profiles of itepekimab and total IL-33 were similar for itepekimab with or without dupilumab, and between East Asian and non-East Asian subgroups. Itepekimab was generally well tolerated, both alone and in combination with dupilumab. The lack of clinical efficacy for itepekimab observed in these studies suggests that IL-33 may not be a key pathogenic driver in moderate-to-severe AD.

Bemarituzumab plus mFOLFOX6 as first-line treatment in East Asian patients with FGFR2b-overexpressing locally advanced or metastatic gastric/gastroesophageal junction cancer: subgroup of FIGHT final analysis

BackgroundIn the FIGHT study (NCT03694522) bemarituzumab, a humanized monoclonal antibody selective for fibroblast growth factor receptor 2b (FGFR2b), plus mFOLFOX6 showed clinically meaningful efficacy in patients with FGFR2b-positive (2+/3+ membranous staining by immunohistochemistry) locally advanced unresectable/metastatic gastric/gastroesophageal cancer (G/GEJC). A meaningful proportion of patients in FIGHT were enrolled in East Asia, reflecting global epidemiology of G/GEJC.MethodsThis subgroup analysis of the global, phase 2, double-blind FIGHT study included all patients enrolled in East Asian sites. Patients were randomized 1:1 to bemarituzumab-mFOLFOX6 (15 mg/kg and one 7.5 mg/kg dose on cycle 1, day 8) or matching placebo-mFOLFOX6. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, and safety. Efficacy was evaluated after a minimum follow-up of 24 months.ResultsThe East Asian subgroup comprised 89 patients (57% of overall study population); 45 were randomized to bemarituzumab-mFOLFOX6 and 44 to placebo-mFOLFOX6. Median PFS (95% confidence interval [CI]) was 12.9 months (8.8–17.9) with bemarituzumab-mFOLFOX6 and 8.2 months (5.6–10.3) with placebo-mFOLFOX6 (HR 0.50, 95% CI 0.29–0.87); median OS (95% CI) was 24.7 months (13.8–33.1) vs 12.9 months (9.3–21.4), respectively (HR 0.56, 95% CI 0.32–0.96). Treatment benefit was more pronounced in patients with FGFR2b-positive G/GEJC in ≥ 10% of tumor cells. No new safety signals were reported.ConclusionIn East Asian patients with FGFR2b-positive advanced/metastatic G/GEJC enrolled in the global FIGHT study, bemarituzumab-mFOLFOX6 showed clinically meaningful outcomes over placebo-mFOLFOX6.

The forkhead box protein P3 gene rs3761548 promoter polymorphism confers a genetic contribution to the risk of preeclampsia: A systematic review and meta-analysis

Various studies have investigated the risk of preeclampsia with the forkhead box protein P3 (FOXP3) gene rs2232365 and rs3761548 polymorphisms. However, the results remained contradictory. A comprehensive literature search was conducted using the Cochrane Library, PubMed, and Web of Science (up to Oct 11, 2021). Meta-analysis was carried out in the R language environment for statistical computing and graphics. A fixed-effect or random-effects model was used according to the statistical significance of heterogeneity among included studies. The pooled odds ratios and corresponding 95% confidence intervals were calculated to estimate the strength of the effect. For the rs2232365 polymorphism, statistical significance was detected neither in the overall population nor among the East Asian and West Asian subgroups. However, for rs3761548, the summarized statistics revealed a significant association between the C allele carriage and preeclampsia risk in the homozygote, heterozygote, and dominant models. The further stratified analysis found this effect might be specific to West-South Asian ethnic subgroups. To sum up, this meta-analysis showed that the FOXP3 rs3761548 polymorphism was significantly associated with preeclampsia susceptibility, and it had a deleterious effect especially in the West-South Asian population. In contrast, rs2232365 may serve as neither a protective nor a risk factor for preeclampsia onset.

Efficacy and Safety of Belimumab in Patients With Lupus Nephritis: Subgroup Analyses of a Phase 3 Randomized Trial in the East Asian Population

Belimumab improved kidney outcomes in patients with active lupus nephritis (LN) in BLISS-LN, leading to its approval in the United States and the European Union. As data on treatment of East Asian patients with LN are limited, we evaluated the efficacy and safety of belimumab in the BLISS-LN East Asian subgroup. Prespecified subgroup analysis of BLISS-LN, a phase 3, placebo-controlled, randomized 104-week trial. Adults with biopsy-proven, active LN were randomized (1:1) to belimumab or placebo, plus standard therapy. Patients were administered intravenous belimumab 10mg/kg, or placebo, plus standard therapy (oral glucocorticoids and either cyclophosphamide for induction followed by azathioprine for maintenance, or mycophenolate mofetil for both induction and maintenance). At the investigator's discretion, 1-3 intravenous pulses of methylprednisolone, 500-1,000mg each, could be administered during induction. The primary end point was primary efficacy renal response (PERR; ie, urinary protein-creatinine ratio≤0.7g/g, estimated glomerular filtration rate no more than 20% below preflare value or≥60mL/min/1.73m2, and no treatment failure) at week 104. Key secondary end points included complete renal response (CRR; urinary protein-creatinine ratio<0.5g/g, estimated glomerular filtration rate no more than 10% below preflare value or≥90mL/min/1.73m2, and no treatment failure) at week 104; PERR at week 52; time to kidney-related event or death; and safety. PERR and CRR were analyzed using a logistic regression model, and time to a kidney-related event or death was analyzed using a Cox proportional hazards regression model. 142 patients from mainland China, Hong Kong, South Korea, and Taiwan were included (belimumab, n=74; placebo, n=68). At week 104, more belimumab than placebo patients achieved PERR (53% vs 37%; OR, 1.76 [95% CI, 0.88-3.51]) and CRR (35% vs 25%; OR, 1.73 [95% CI, 0.80-3.74]). At week 52, more belimumab than placebo patients achieved PERR (62% vs 37%; OR, 2.74 [95% CI, 1.33-5.64]). Belimumab reduced the risk of a kidney-related event or death compared with placebo at any time (HR, 0.37 [95% CI, 0.15-0.91]). Safety was similar across treatment groups. Small sample size and lack of formal significance testing. Safety and efficacy profiles were consistent with BLISS-LN overall population, supporting benefits of belimumab treatment in the East Asian subgroup with LN. This study was funded by GSK (GSK study no. BEL114054). Registered at ClinicalTrials.gov with study number NCT01639339.

Safety and tolerability of linagliptin in Asians with type 2 diabetes: a pooled analysis of 4457 patients from 21 randomized, double-blind, placebo-controlled clinical trials

ABSTRACT Background Safety and tolerability of glucose-lowering drugs is a key consideration for use in type 2 diabetes (T2D). We evaluated the safety and tolerability of the dipeptidyl peptidase-4 inhibitor linagliptin in Asian patients with T2D. Research design and methods This was a post-hoc, descriptive pooled analysis of 21 randomized, double-blind, placebo-controlled clinical trials of linagliptin in T2D patients lasting ≤52 weeks. We evaluated adverse events (AEs) and laboratory parameters in Asian participants living in Asia, both overall and in the East Asian subgroup. Results This analysis included 4457 Asian patients overall (2712 receiving linagliptin; 1745 receiving placebo) and 3057 (68.6%) East Asians. AEs were reported in 1510 (55.7%) Asian patients receiving linagliptin and 1032 (59.1%) receiving placebo but were considered drug-related in only 13.0% of each group. Serious AEs occurred in 109 (4.0%) linagliptin patients and 90 (5.2%) placebo patients. The most common AEs were nasopharyngitis (6.4% linagliptin, 7.3% placebo), upper respiratory tract infection (5.7% linagliptin, 6.5% placebo), and hypoglycemia (7.3% linagliptin, 6.3% placebo). One linagliptin patient had pancreatitis; none had bullous pemphigoid. No clinically relevant mean changes in laboratory parameters occurred. These findings were consistent in East Asians. Conclusions Linagliptin is well tolerated in Asian T2D patients, including East Asians, with low risk for AEs.

Different Associations Between CDKAL1 Variants and Type 2 Diabetes Mellitus Susceptibility: A Meta-analysis.

Background: CDK5 regulatory subunit associated protein 1 like 1 (CDKAL1) is a major pathogenesis-related protein for type 2 diabetes mellitus (T2DM). Recently, some studies have investigated the association of CDKAL1 susceptibility variants, including rs4712523, rs4712524, and rs9460546 with T2DM. However, the results were inconsistent. This study aimed to evaluate the association of CDKAL1 variants and T2DM patients. Methods: A comprehensive meta-analysis was performed to assess the association between CDKAL1 SNPs and T2DM among dominant, recessive, additive, and allele models. Results: We investigated these three CDKAL1 variants to identify T2DM risk. Our findings were as follows: rs4712523 was associated with an increased risk of T2DM for the allele model (G vs A: OR = 1.172; 95% CI: 1.103–1.244; p < 0.001) and dominant model (GG + AG vs AA: OR = 1.464; 95% CI: 1.073–1.996; p = 0.016); rs4712524 was significantly associated with an increased risk of T2DM for the allele model (G vs A: OR = 1.146; 95% CI: 1.056–1.245; p = 0.001), additive model (GG vs AA: OR = 1.455; 95% CI: 1.265–1.673; p < 0.001) recessive model (GG vs AA + AG: OR = 1.343; 95% CI: 1.187–1.518; p < 0.001) and dominant model (GG + AG vs AA: OR = 1.221; 95% CI: 1.155–1.292; p < 0.001); and rs9460546 was associated with an increased risk of T2DM for the allele model (G vs T: OR = 1.215; 95% CI: 1.167–1.264; p = 0.023). The same results were found in the East Asian subgroup for the allele model. Conclusions: Our findings suggest that CDKAL1 polymorphisms (rs4712523, rs4712524, and rs9460546) are significantly associated with T2DM.

Association between RGS4 gene polymorphisms and schizophrenia: A protocol for systematic review and meta-analysis.

Background:Schizophrenia is a complex brain disorder, the pathogenesis of which remains unclear. Regulator of G-protein signaling 4 is regarded as a candidate gene for schizophrenia risk. The association between the regulator of G-protein signaling 4 gene and the risk of schizophrenia is complicated and controversial, thus, an updated meta-analysis is needed.Methods:A search strategy using Medical Subject Headings was developed in English (PubMed, SZGene) and Chinese (CNKI, Wanfang, and Weipu) databases. Inclusion and exclusion criteria were used to screen for eligible studies. Parameters, such as P value of Hardy–Weinberg equilibrium, odds ratios, 95% confidence intervals, P values of association, heterogeneity (Ph), and publication bias, were analyzed by the Stata software using a random effects model. Subgroup analyses were performed to detect heterogeneity.Results:There were 15 articles regarding rs10917670 (8046 cases and 8837 controls), 16 regarding rs951436 (8990 cases and 10,568 controls), 15 regarding rs951439 (7995 cases and 8646 controls), 15 regarding rs2661319 (8320 cases and 9440 controls), and 4 regarding rs10759 (2752 cases and 2866 controls). The frequencies of rs10917670 and rs951439 were not significantly different between the case and control groups (P > .05). As shown by the East Asian and hospital-based subgroup analyses, the genotype TT of rs951436 might be related to the risk of schizophrenia. The genotypes CC + CT of rs2661319 and CC + CA of rs10759 were statistically different between the 2 groups, and the East Asian population contributed to these differences.Conclusion:The genotypes CC + CT of rs2661319 and CC + CA of rs10759 might be associated with the risk of schizophrenia.

Association between IL-1B (-511)/IL-1RN (VNTR) polymorphisms and type 2 diabetes: a systematic review and meta-analysis.

Interleukin-1 (IL-1) plays an essential role in the immune pro-inflammatory process, which is regarded as one of many factors in the development of type 2 diabetes mellitus (T2DM). Several case-control studies have illustrated the association of the IL-1B (-511) (rs16944, Chr 2:112,837,290, C/T Intragenic, Transition Substitution) and IL-1RN (VNTR) (gene for IL-1 receptor antagonist, IL-1RA, 86 bp tandem repeats in intron 2) polymorphisms with T2DM risk. However, the results were inconsistent and inconclusive. We performed a meta-analysis (registry number: CRD42021268494) to assess the association of the IL-1B (-511) and IL-1RN (VNTR) polymorphisms with T2DM risk. Random-effects models were applied to calculate the pooled ORs (odds ratios) and 95% CIs (confidence intervals) to test the strength of the association in the overall group and subgroups stratified by ethnicity, respectively. Between-study heterogeneity and publication bias were evaluated by the Q-test, I2 statistic, Harbord test, and Peters test accordingly. Sensitivity analyses were also performed. A total of 12 publications evaluating the association of IL-1B (-511) and IL-1RN (VNTR) polymorphisms with the risk of T2DM development were included. The meta-analysis showed that IL-1RN (VNTR) was related to the increasing development of T2DM risk in the recessive model (OR = 1.62, 95% CI [1.09–2.42], Phet = 0.377, Pz = 0.018) and in the homozygous model (OR = 2.02, 95% CI [1.07–3.83], Phet = 0.085, Pz = 0.031), and the IL-1RN 2* allele was found a significant association with evaluated T2DM risk in all ethnicities (OR = 2.08, 95% CI [1.43–3.02], Phet < 0.001, Pz < 0.001) and in EA (OR = 2.01, 95% CI [1.53–2.66], Phet = 0.541, Pz < 0.001). Moreover, stratification by ethnicity revealed that IL-1B (-511) was associated with a decreased risk of T2DM in the dominant model (OR=0.76, 95% CI [0.59–0.97], Phet = 0.218, Pz = 0.027) and codominant model (OR = 0.73, 95% CI [0.54–0.99], Phet = 0.141, Pz = 0.040) in the East Asian (EA) subgroup. Our results suggest that the IL-1RN 2* allele and 2*2* homozygous polymorphism are strongly associated with increasing T2DM risk and that the IL-1B (-511) T allele polymorphism is associated with decreasing T2DM risk in the EA subgroup.

P-198: Isatuximab plus Carfilzomib and Dexamethasone in East Asian patients with relapsed Multiple Myeloma: IKEMA subgroup analysis

<h3>Background</h3> Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) plus carfilzomib and dexamethasone (Kd) significantly improved progression-free survival (PFS) compared with Kd in patients (pts) with relapsed multiple myeloma (RMM) (hazard ratio [HR] 0.53; 99% confidence interval [CI] 0.32–0.89; P=0.0007). We evaluated efficacy and safety of Isa-Kd in East Asian pts (19 Japanese, 27 Korean) from IKEMA study. <h3>Methods</h3> RMM pts who received 1–3 prior lines of therapy were stratified to receive Isa-Kd or Kd. Isa-Kd arm received Isa (10 mg/kg intravenously) weekly for 4 weeks, then every 2 weeks. Both arms received K (20 mg/m2 Days 1–2, 56 mg/m2 thereafter) twice-weekly for 3 of 4 weeks, and d (20 mg) twice-weekly. Treatment continued until disease progression or unacceptable adverse events (AEs). The primary endpoint was PFS. Key secondary endpoints were overall response rate (ORR), very good partial response or better (≥VGPR), minimal residual disease negativity (MRD–), and complete response (CR) rates. Complete renal response (CRr, increase in eGFR from <50 mL/min/1.73 m2 at baseline to ≥60 mL/min/1.73 m2 in at least one post-baseline assessment) was also measured. <h3>Results</h3> East Asian pts (25 Isa-Kd, 21 Kd) were randomized. Pt characteristics were similar in the East Asian subgroup and the intent to treat (ITT) population (N=302). Median age (Isa-Kd 64.0 [range 45–83] years vs Kd 60.0 [33–73] years); median prior lines Isa-Kd 2.0 (1–3) vs Kd 1.0 (1–3); refractory to lenalidomide 16.0% Isa-Kd vs 47.6% Kd; refractory to proteasome inhibitor 20.0% Isa-Kd vs 33.3% Kd; high-risk cytogenetics 48.0% Isa-Kd vs 42.9% Kd. After a median follow-up of 20.7 months, PFS HR (0.64; 95% CI: 0.23–1.76) favored Isa-Kd, consistent with the HR in ITT population. ORR was high in both arms (Isa-Kd 88.0% vs Kd 81.0%); however, addition of Isa to Kd improved ≥VGPR (Isa-Kd 80.0% vs Kd 52.4%), MRD– (Isa-Kd 44.0% vs Kd 9.5%), and CR (Isa-Kd 44.0% vs Kd 23.8%) rates in East Asian pts, consistent with the ITT population (Isa-Kd vs Kd) (≥VGPR: 72.6% vs 56.9%; MRD–: 29.6% vs 13.0%; CR: 39.7% vs 27.6%). Renal response (CRr) was 100% (3/3 pts) in Isa-Kd vs 0% (0/2 pts) in Kd arm. Safety profile of Isa-Kd in East Asian pts was similar to the ITT population: Grade ≥3 AEs were observed in 79.2% Isa-Kd vs 55.0% Kd pts, serious TEAEs in 45.8% Isa-Kd vs 50.0% Kd pts, TEAEs fatal during study treatment in 0% Isa-Kd vs 5.0% Kd pts, and TEAEs leading to treatment discontinuation in 4.2% Isa-Kd vs 10.0% Kd pts. Overall, 64.0% Isa-Kd vs 42.9% Kd pts were still on treatment. <h3>Conclusions</h3> Efficacy and safety results of Isa-Kd in East Asian pts are consistent with overall IKEMA population; similar treatment effect for PFS, ≥VGPR, MRD–, and CR rates was reported in favor of Isa-Kd without an increase in the number of pts with serious TEAEs, TEAEs fatal during study treatment, or leading to discontinuations. Isa-Kd is a potential new treatment option for East Asian pts with RMM. © 2021 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2021 ASCO Annual Meeting. All rights reserved.

Variants of candidate genes associated with the risk of obstructive sleep apnea

The researches on the associations between different candidate genes and obstructive sleep apnea (OSA) are inconsistent. Here, we performed a comprehensive qualitative and quantitative analysis to estimate the contribution of variants from candidate genes to the risk of OSA. Qualitative analysis was conducted to find the relationships for all included genes. Then, quantitative analysis of both allele models and genotype models was applied to evaluate the risk variants for OSA. Furthermore, a similar analysis was performed in different ethnic groups. We included 152 publications containing 75genes for qualitative analysis. Among them, we included 93 articles containing 28 variants from 16genes for quantitative analysis. Through allele models, we found 10 risk variants for OSA (rs1801133 of MTHFR, ɛ4 of ApoE, -1438G/A of 5-HT2A, -308G/A of TNF-α, Pro1019Pro of LEPR, rs1130864 and rs2794521 of CRP, D/I of ACE, LPR and VNTR of 5-HTT) with the ORs of 1.21-2.07 in global population. We found that the variant of ɛ2 of ApoE could uniquely decrease the risk of OSA in the East Asian subgroup, while the other 6 variants, including ɛ4 in ApoE, -308G/A in TNF-α, Pro1019Pro in LEPR, D/I in ACE, LPR and VNTR in 5-HTT, could increase the risk of OSA. As for the European subpopulation, we only found that -308G/A in TNF-α could increase the risk for OSA. Eleven variants from the candidate genes are associated with the risk of OSA, which also show ethnicity differences in East Asian and European subgroups.

A targeted ancestry informative InDels panel on capillary electrophoresis for ancestry inference in Asian populations.

CE is the primary methodology used in forensic DNA typing. Alleles of commonly used types of genetic markers could be separated and detected via CE based on dye color and migration time. Insertion/deletion (InDel) is an ideal genetic marker for forensic DNA analysis due to their abundance in the human genome, low mutation rate, availability of their allele types via CE, and elimination of stutter peaks. Moreover, InDels could be used as ancestry informative markers since allele frequencies of InDels is different among geographically separated populations. Several ancestry informative insertion/deletion panels have been established based on CE platform to achieve the intercontinental populations distinction. However, improvements to differentiate intracontinental populations is few. In this study, 21 InDels with fixation index (FST ) > 0.15were selected and assembled into one ancestry informative insertion/deletion panel. Using well-designed primers, those 21 InDels could be amplified successfully and genotyped on the CE platform accurately and completely. The panel showed a large FST distance distinction among the ten Asian populations. Using clustering analysis, ten Asian populations were classified into three subgroups: East Asian, Southeast Asian, and South Asian subgroups. To evaluate the panel's capability in ancestry inference, a validation experiment was undertaken with 319 individuals from four geographically separated populations in China. Four Chinese populations were classified into different ancestry subgroups and 81.8% test individuals' ancestry could be inferred correctly. Our result showed that development of high ancestry informative InDels panel based on CE platform is a potential for individual ancestry inference among intracontinental populations.

Isatuximab plus carfilzomib and dexamethasone in east Asian patients with relapsed multiple myeloma: IKEMA subgroup analysis.

e20015 Background: The Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) plus carfilzomib and dexamethasone (Kd) significantly improved progression-free survival (PFS) compared with Kd in patients (pts) with relapsed multiple myeloma (RMM) (hazard ratio [HR] 0.53; 99% confidence interval [CI] 0.32–0.89; P= 0.0007). We evaluated the efficacy and safety of Isa-Kd in the East Asian patients (19 Japanese, 27 Korean). Methods: RMM pts who received 1-3 prior lines of therapy were stratified to receive Isa-Kd or Kd. Isa-Kd arm received Isa (10 mg/kg intravenously) weekly for 4 weeks, then every 2 weeks. Both arms received K (20 mg/m2 days 1-2, 56 mg/m2 thereafter) twice-weekly for 3 of 4 weeks, and d (20 mg) twice-weekly. Treatment continued until disease progression or unacceptable adverse events (AE). The primary endpoint was prolongation of PFS. Key secondary endpoints included; very good partial response or better (≥VGPR), complete response (CR) rate and minimal residual disease negativity (MRD–) rate. Results: East Asian pts (25 Isa-Kd, 21 Kd) were randomized. Pt characteristics were similar in the East Asian subgroup compared with the intent to treat (ITT) population (N = 302). Median age (Isa-Kd 64.0 [range 45–83] years vs Kd 60.0 [range 33–73] years); median prior lines Isa-Kd 2.0 (range 1–3) vs Kd 1.0 (range 1–3); refractory to lenalidomide 16.0% Isa-Kd vs 47.6% Kd; refractory to PI 20.0% Isa-Kd vs 33.3% Kd; high-risk cytogenetics 48.0% Isa-Kd vs 42.9% Kd. After a median follow-up of 20.7 months, the addition of Isa to Kd improved ≥VGPR, CR and MRD– rates (Table). The HR 0.64 (95%CI: 0.231-1.764) for disease progression or death favored Isa-Kd. Grade ≥3 AEs were observed in 79.2% Isa-Kd vs 55.0% Kd pts, serious TEAEs in 45.8% Isa-Kd vs 50.0% Kd; TEAEs leading to treatment discontinuation were lower in the Isa-Kd group (4.2% Isa-Kd vs 10.0% Kd). Overall, 64.0% Isa-Kd vs 42.9% Kd pts were still receiving treatment. Conclusions: Efficacy and safety results of Isa-Kd in East Asian pts are consistent with the results of the overall IKEMA population, in which significantly better efficacy (PFS, CR, ≥VGPR and MRD– rate) was reported in favor of Isa-Kd without an increase in the number of patients with serious TEAEs or discontinuations. Isa-Kd is a potential treatment option for East Asian pts with RMM. Clinical trial information: NCT03275285. [Table: see text]

MTHFR 1298A>C Substitution is a Strong Candidate for Analysis in Recurrent Pregnancy Loss: Evidence from 14,289 Subjects.

We undertook meta-analyses on MTHFR 1298A>C substitution for critically evaluating its association with recurrent pregnancy loss (RPL). MTHFR genotype data for 5888 cases and 8401 controls from 39 studies were pooled to perform thismeta-analyses. Genotype data were screened, scrutinized, pooled, analysed and subjected to sensitivity analysis to carefully evaluate the association between MTHFR 1298A>C and recurrent pregnancy loss. Genetic associations were sought using dominant, recessive and co-dominant models of genetic testingwith odds ratio and 95%Confidence interval (CI) as the effect measures. Further analyses were undertaken by classifying the studies into Caucasian and East Asian sub-groups. Genetic heterogeneity was tested before pooling the data across studies. For assessing publication bias, Egger's intercept test was undertaken. We found a significant association of 1298A>C substitution with increased risk of RPL in the dominant (P=0.000; OR = 1.58; 95% CI =1.25-1.99) as well as recessive (P=0.000; OR = 1.66; 95% CI =1.25-2.20) models. In sub-group analysis, we observed a significant association of the polymorphism with RPL in the Caucasian populations using dominant (P=0.000; OR = 1.98; 95% CI =1.42-2.76) and recessive (P=0.000; OR = 2.20; 95% CI =1.49-3.24) models. However, this substitution showed no association with RPL in the East Asian populations (P=0.149; OR = 1.187; 95% CI =0.94-1.50). MTHFR 1298A>C substitution shows association with the risk of recurrent pregnancy loss. The association is in a population-specific manner with the substitution being a strong risk factor only in the Caucasian populations.

Customized birth-weight centiles and placenta-related fetal growth restriction.

The value of using customized birth-weight centiles to improve the diagnostic accuracy for fetal growth restriction (FGR), in comparison with using population-based charts, remains a matter of debate. One potential explanation for the conflicting data is that most studies used measures of perinatal mortality and morbidity as proxies for placenta-mediated FGR, many of which are not specific and may be confounded by other factors such as prematurity. The aim of this study was to compare the diagnostic accuracy of small-for-gestational age (SGA) at birth, defined according to customized vs population-based charts, for associated abnormal placental pathology. This was a secondary analysis of data from a prospective cohort study on risk factors for placenta-mediated complications and abnormal placental pathology in low-risk nulliparous women. All placentae were sent for detailed histopathological examination by two perinatal pathologists. The primary exposure was SGA, defined as birth weight < 10th centile for gestational age using either a customized (SGAcust ) or a population-based (SGApop ) birth-weight reference. The outcomes of interest were one of three types of abnormal placental pathology associated with FGR: maternal vascular malperfusion (MVM), chronic villitis and fetal vascular malperfusion (FVM). Adjusted relative risks (aRR) with 95% CIs were estimated using modified Poisson regression analysis, with adjustment for smoking, body mass index and aspirin treatment. A total of 857 nulliparous women met the study criteria. The proportions of infants identified as SGA based on the customized and population-based charts were 12.6% (108/857) and 11.4% (98/857), respectively. A diagnosis of SGA using either customized or population-based charts was associated with an increased risk of any placental pathology (aRR, 3.04 (95% CI, 2.29-4.04) and 1.60 (95% CI, 1.10-2.31), respectively) and MVM pathology (aRR, 12.33 (95% CI, 6.60-23.03) and 5.29 (95% CI, 2.87-9.76), respectively). SGAcust , but not SGApop , was also associated with an increased risk for chronic villitis (aRR, 1.85 (95% CI, 1.07-3.18)) and FVM pathology (aRR, 2.48 (95% CI, 1.25-4.93)). SGAcust had a higher detection rate for any placental pathology (30.3% vs 17.1%; P < 0.001), MVM pathology (63.2% vs 39.5%; P = 0.003) and chronic villitis (20.8% vs 8.3%; P = 0.007) than did SGApop , for a similar false-positive rate. This was mainly the result of a higher detection rate for abnormal pathology in the white and East-Asian subgroups and a lower false-positive rate for abnormal pathology in the South-Asian subgroup by SGAcust than by SGApop . In addition, pregnancies in the SGAcust group, but not those in the SGApop group, were more likely to be complicated by preterm birth and a low 5-min Apgar score than were the corresponding non-SGA group. These findings suggest that customized birth-weight centiles may be superior to population-based birth-weight centiles in detecting FGR that is due to underlying placental disease. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Teriparatide in East Asian Postmenopausal Women with Osteoporosis in a Real-World Setting: A Baseline Analysis of the Asia and Latin America Fracture Observational Study (ALAFOS).

PurposeThe aim of this analysis is to describe the baseline characteristics of patients who are prescribed teriparatide for the treatment of postmenopausal osteoporosis in a real-world setting in East Asia.Patients and MethodsThe Asia and Latin America Fracture Observational Study (ALAFOS) is a prospective, multinational, observational study designed to evaluate real-world use of teriparatide in the treatment of postmenopausal osteoporosis in 20 countries across Asia, Latin America, the Middle East, and Russia. This subregional analysis focuses on the East Asian subpopulation of the ALAFOS study. Here we report baseline clinical characteristics, details regarding the history of fractures, risk factors for osteoporosis, comorbidities, osteoporosis treatment, and health-related quality of life in patients enrolled in China, Hong Kong, South Korea, and Taiwan.ResultsThe East Asian subgroup of ALAFOS included 1136 postmenopausal women, constituting 37.5% (1136/3031) of the overall ALAFOS patient population. The mean (SD) age was 75.0 (9.6) years. The mean (SD) bone mineral density T-scores were −3.11 (1.54), −2.58 (1.11), and −2.86 (1.09) at the lumbar spine, total hip, and femoral neck, respectively; 69.6% of patients had experienced at least one fragility fracture and 40.4% had experienced ≥2 fragility fractures after 40 years of age. Overall, 63.3% of patients had used medications for osteoporosis in the past. The mean (SD) EQ-5D-5L Visual Analog Scale (VAS) score at baseline was 59.7 (20.8); the mean (SD) back pain numeric rating scale score for worst pain in the last 24 hrs was 5.2 (3.2).ConclusionOur results indicate that patients who are prescribed teriparatide in East Asia were elderly women with severe osteoporosis, low bone mineral density, high prevalence of fractures, back pain and poor health-related quality of life. Most of the patients received teriparatide as a second-line treatment.

269O - Efficacy and safety of isatuximab plus pomalidomide and dexamethasone in East Asian patients with relapsed/refractory multiple myeloma: A subgroup analysis of ICARIA-MM study

BackgroundThe phase 3 ICARIA study demonstrated that isatuximab (Isa) plus pomalidomide and dexamethasone (Pd) significantly improved progression free survival (PFS) compared with Pd in patients (pts) with relapsed/refractory multiple myeloma (RRMM) (HR = 0.596, 95%CI 0.44-0.81, P = 0.001). We evaluated the efficacy/safety of Isa-Pd in the East Asian pts (13 Japanese, 9 Korean and 14 Taiwanese pts) of ICARIA. MethodsRRMM pts who had received ≥2 prior lines of therapies, including lenalidomide (len) and at least a proteasome inhibitor (PI), and were refractory to their last therapy were enrolled. Pts were randomized into either Isa-Pd arm who received Isa 10 mg/kg IV weekly for the first 4 weeks (wks) followed by biweekly or Pd arm, and all pts received Pom (4mg PO days 1-21) and dex (40mg [20mg if older than 75 yrs] PO or IV weekly) in 28 day cycle until disease progression or unacceptable toxicity. ResultsData from 36 East Asian pts (21 Isa-Pd, 15 Pd) including Japanese pts (9 Isa-Pd, 4 Pd) were analyzed. Patient’s characteristics were similar in the East Asian subgroup and the entire population of ICARIA study (n = 307). Of these pts, median age: 65 (range, 41-85) yrs; median prior lines of therapy: 3 (range, 2-7); 91.7% and 69.4% were refractory to len and PI, respectively; and 13.9% had high-risk cytogenetics. After median follow-up of 11.6 months, median PFS was not reached yet in Isa-Pd arm and was 7.9 months in Pd arm (HR 0.517 [95% CI 0.19-1.39]). ORR (≥PR) was 71.4% in Isa-Pd arm 60% in Pd arm. The VGPR rate or better was 61.9% and 13.3% in Isa-Pd and Pd arm, respectively. Median time to first response was 32 days and 59 days for Isa-Pd and Pd arm, respectively. Grade ≥3 AEs were observed in 90.5% and 73.3% pts in Isa-Pd and Pd arm, respectively and which caused 9.5% pts in the Isa-Pd arm and 0 % in Pd arm to discontinue their treatment. Infusion associated reactions were reported in 57.1% pts receiving Isa-Pd but none of them were grade 3-4. ConclusionsThis subgroup analysis of ICARIA demonstrates that the efficacy and safety of Isa-Pd in East Asian population, including Japanese pts, are comparable with the entire population of ICARIA. Isa-Pd is a novel treatment option for East Asian pts with RRMM. Clinical trial identificationClinical trial information: NCT02990338. Legal entity responsible for the studySanofi. FundingSanofi. DisclosureK. Sunami: Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: GlaxoSmithKline; Speaker Bureau / Expert testimony: Janssen Pharmaceutical. M. Matsumoto: Speaker Bureau / Expert testimony: Celgene Co., LTD; Speaker Bureau / Expert testimony: Janssen Pharmaceutical Co., LTD; Speaker Bureau / Expert testimony: Bristol-Myers Squibb K.K.; Speaker Bureau / Expert testimony: Ono Pharmaceutical Co., LTD. C. Shimazaki: Speaker Bureau / Expert testimony: Ono Pharmaceutical Co. Ltd.; Speaker Bureau / Expert testimony: Celgen Co. Ltd.; Speaker Bureau / Expert testimony: Fujimoto Pharmaceutical Co. Ltd. F. Campana: Full / Part-time employment: Sanofi. K. Tada: Full / Part-time employment: Sanofi. S. Iida: Speaker Bureau / Expert testimony: Ono; Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Celgene; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Daiichi-Sankyo; Speaker Bureau / Expert testimony: Chugai; Speaker Bureau / Expert testimony: Kyowa Hakko Kirin; Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Daiichi Sankyo; Speaker Bureau / Expert testimony: Gilead; Speaker Bureau / Expert testimony: AbbVie. K. Suzuki: Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Celgene; Speaker Bureau / Expert testimony: Ono; Speaker Bureau / Expert testimony: Fujimoto; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony: Sumitomo Dainippon ; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Sanofi. All other authors have declared no conflicts of interest.

A systematic review and meta-analysis of the association between HOTAIR polymorphisms and susceptibility to breast cancer.

Many studies are drawing attention to the associations of HOTAIR polymorphisms and susceptibility to breast cancer, while the results remain inconsistent. We conducted a meta-analysis on the association of four common HOTAIR polymorphisms with breast cancer susceptibility. Eligible published articles were searched in PubMed, Embase, Cochrane library databases and Web of Science databases up to July 2019. Odds ratios with 95% confidence intervals were used to identify potential links between lncRNA HOTAIR polymorphisms and the risk of breast cancer. Our results showed no significance in all genetic models of all four SNPs. Pooled analyses detected crucial links between the rs1899663 polymorphism and decreased susceptibility to breast cancer in five genetic models rather than the dominant model in the hospital-based control subgroup. For the rs920778 polymorphism, we found that it significantly decreased breast cancer risk under recessive, homozygous and heterozygous models within the west Asian subgroup and increased breast cancer risk under allele and dominant models within the East Asian subgroup. Additionally, rs920778 polymorphism decreased breast cancer risk under recessive and heterozygous models in the hospital-based control subgroup. However, no significant association was observed between the rs4759314 polymorphism and breast cancer risk in overall and stratified analyses. For rs12826786 polymorphism, it was greatly associated with decreased breast cancer risk under recessive, homozygous and heterozygous models in the hospital-based control subgroup. HOTAIR rs920778, rs1899663 and rs12826786 polymorphisms may contribute to breast cancer susceptibility.

Association of Polymorphisms at the SIX1-SIX6 Locus With Primary Open-Angle Glaucoma.

To evaluate the association of single-nucleotide polymorphisms (SNPs) in the SIX1-SIX6 locus with primary open-angle glaucoma (POAG) through a systematic review and meta-analysis from 22 studies. To our knowledge, all case-control association studies on SNPs in the SIX1-SIX6 locus and POAG reported up to August 30, 2018, in PubMed, Embase, and Web of Science were retrieved. Unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for each SNP were calculated using a fixed- or random-effect model according to interstudy heterogeneity. This meta-analysis involved 12 SNPs in SIX1-SIX6 reported in 22 studies. The association of rs10483727 with POAG has been presented in 16 studies involving 14,402 patients and 27,425 controls, whereas rs33912345 has been investigated in 12 studies involving 10,563 patients and 16,740 controls. Meta-analyses revealed significant associations of these two SNPs with POAG in the pooled populations under all genetic models. Stratified analyses by population detected significant association of both SNPs in the East Asian and Caucasian subgroups, but not in South Asian or African subgroups. Among the other SNPs that were reported by up to four cohorts of East Asian and African ancestries, only rs12436579 showed a significant association in the meta-analysis (OR = 0.79, P = 1.08 × 10-4). This meta-analysis confirmed the association of rs10483727 and rs33912345 in SIX1-SIX6 with POAG. The associations of both SNPs were specifically detected in East Asian and Caucasian cohorts, rather than in South Asian and African cohorts, suggesting an ethnic difference. SNP rs12436579 is a candidate variant for the disease that awaits validation in other populations.

1188-P: Glycemic Efficacy of Sitagliptin in East Asian Populations: A Pooled Analysis

The efficacy/safety of sitagliptin (SITA) has been studied in global populations. This post hoc pooled analysis of 20 placebo (PBO)-controlled studies reports data collected specifically in East Asian populations (EAP). Results were summarized for overall EAP and subgroups defined by geography. Change from baseline in A1C was analyzed at week 12 using ANCOVA model with treatment, study, and baseline A1C terms. A1C values following initiation of rescue medication were excluded. Missing A1C values were imputed using LOCF method. Baseline characteristics were generally balanced across treatments (mean A1C 8.5%, age 55-56 years, BMI 25 kg/m2, FPG 177-179 mg/dL, duration T2D 7-8 years). After 12 weeks of SITA, all populations showed significant A1C reductions vs. PBO (Table) and the largest PBO-adjusted reduction was seen in the Japan subgroup. PBO treatment was associated with reductions in A1C in China Mainland (CM), but with increases in Japan. The percentages of SITA-treated pts with A1C &amp;lt;7% were 18.9%, 14.2%, 37.4% and 30.4% for overall EAP, CM, Japan and Other East Asian subgroups, respectively (all p&amp;lt;0.001 vs. PBO). The incidences of hypoglycemia (i.e., symptomatic/asymptomatic) were 13/981 [1.3%] and 5/816 [0.6%] for SITA and PBO, respectively. These results are consistent with previous findings in global populations. Disclosure J.M. Conceicao: Employee; Self; Merck Sharp &amp; Dohme Corp. Stock/Shareholder; Self; Merck Sharp &amp; Dohme Corp. C.D. Gonzalez: Employee; Self; Merck &amp; Co., Inc. Stock/Shareholder; Self; Merck &amp; Co., Inc. S.S. Engel: Employee; Self; Merck &amp; Co., Inc. Stock/Shareholder; Self; Merck &amp; Co., Inc. J. Ahn: Employee; Self; Merck Sharp &amp; Dohme Corp. Stock/Shareholder; Self; Merck Sharp &amp; Dohme Corp. S. Tokita: Employee; Self; Merck Sharp &amp; Dohme Corp. Stock/Shareholder; Self; Merck Sharp &amp; Dohme Corp. Y. Zhang: Employee; Self; Merck Sharp &amp; Dohme Corp. R. Zhang: Employee; Self; Merck Sharp &amp; Dohme Corp. R.L. Lam: Employee; Self; Merck &amp; Co., Inc. A. Pong: None. Funding Merck &amp; Co., Inc.

Everolimus for the treatment of advanced gastrointestinal or lung nonfunctional neuroendocrine tumors in East Asian patients: a subgroup analysis of the RADIANT-4 study.

BackgroundIn RADIANT-4, everolimus showed an improvement of 7.1 months in median progression-free survival (PFS) vs placebo among patients with advanced, well-differentiated, nonfunctional neuroendocrine tumors (NETs) of gastrointestinal (GI) or lung origin. The present analysis focuses on the effect of everolimus on the East Asian-subgroup population of the RADIANT-4 study.MethodsPatients were randomized to receive everolimus 10 mg/day or matching placebo. The primary end point was PFS (central review). Secondary end points were overall response rate, safety, and tolerability.ResultsAmong 302 patients enrolled in RADIANT-4, 46 were included in the East Asian subgroup (everolimus, n=28; placebo, n=18) analysis. Everolimus was associated with an 82% reduction in the relative risk of disease progression or death (HR 0.18, 95% CI 0.09–0.38). The median PFS (central review) in this subgroup was 11.2 months with everolimus vs 3.1 months with placebo. Adverse events (AEs) occurred in all 28 patients treated with everolimus and ten patients receiving placebo. The majority of these AEs were grade 1 or 2. Most commonly reported ($30% of incidence) drug-related AEs of any grade included stomatitis (75%, n=21) and rash (43%, n=12) in the everolimus arm.ConclusionEverolimus demonstrated a clinically meaningful PFS benefit in the East Asian population. The safety findings were consistent with the known safety profile of everolimus. These results support the use of everolimus in the East Asian population with advanced, nonfunctional NETs of GI or lung origin.