Abstract Objective The recurrence rate of anti‐SSA/Ro–associated congenital heart block (CHB) is 17%. Sustained reversal of third‐degree block has never been achieved. Based on potential reduction of maternal autoantibody titers as well as fetal inflammatory responses, intravenous immunoglobulin (IVIG) was evaluated as preventive therapy for CHB. Methods A multicenter, prospective, open‐label study based on Simon's 2‐stage optimal design was initiated. Enrollment criteria included the presence of anti‐SSA/Ro antibodies in the mother, birth of a previous child with CHB/neonatal lupus rash, current treatment with ≤20 mg/day of prednisone, and <12 weeks pregnant. IVIG (400 mg/kg) was given every 3 weeks from week 12 to week 24 of gestation. The primary outcome was the development of second‐degree or third‐degree CHB. Results Twenty mothers completed the IVIG protocol before the predetermined stopping rule of 3 cases of advanced CHB in the study was reached. CHB was detected at 19, 20, and 25 weeks; none of the cases occurred following the finding of an abnormal PR interval on fetal Doppler monitoring. One of these mothers had 2 previous children with CHB. One child without CHB developed a transient rash consistent with neonatal lupus. Sixteen children had no manifestations of neonatal lupus at birth. No significant changes in maternal titers of antibody to SSA/Ro, SSB/La, or Ro 52 kd were detected over the course of therapy or at delivery. There were no safety issues. Conclusion This study establishes the safety of IVIG and the feasibility of recruiting pregnant women who have previously had a child with CHB. However, IVIG at low doses consistent with replacement does not prevent the recurrence of CHB or reduce maternal antibody titers.
Calix[4]arene compound 0118 is an angiostatic agent that inhibits tumor growth in mice. Although 0118 is a topomimetic of galectin-1-targeting angiostatic amphipathic peptide Anginex, we had yet to prove that 0118 targets galectin-1. Galectin-1 is involved in pathological disorders like tumor endothelial cell adhesion and migration and therefore presents a relevant target for therapeutic intervention against cancer. Here, (15)N-(1)H HSQC NMR spectroscopy demonstrates that 0118 indeed targets galectin-1 at a site away from the lectin's carbohydrate binding site and thereby attenuates lactose binding to the lectin. Flow cytometry and agglutination assays show that 0118 attenuates binding of galectin-1 to cell surface glycans, and the inhibition of cell proliferation by 0118 is found to be correlated with the cellular expression of the lectin. In general, our data indicate that 0118 targets galectin-1 as an allosteric inhibitor of glycan/carbohydrate binding. This work contributes to the clinical development of antitumor calixarene compound 0118.
Galectin-3 (Gal-3) is a multifunctional lectin, unique to galectins by the presence of a long N-terminal tail (NT) off of its carbohydrate recognition domain (CRD). Many previous studies have investigated binding of small carbohydrates to its CRD. Here, we used nuclear magnetic resonance spectroscopy (15N–1H heteronuclear single quantum coherence data) to assess binding of 15N-Gal-3 (and truncated 15N-Gal-3 CRD) to several, relatively large polysaccharides, including eight varieties of galactomannans (GMs), as well as a β(1 → 4)-polymannan and an α-branched mannan. Overall, we found that these polysaccharides with a larger carbohydrate footprint interact primarily with a noncanonical carbohydrate-binding site on the F-face of the Gal-3 CRD β-sandwich, and to a less extent, if at all, with the canonical carbohydrate-binding site on the S-face. While there is no evidence for interaction with the NT itself, it does appear that the NT somehow mediates stronger interactions between the Gal-3 CRD and the GMs. Significant Gal-3 resonance broadening observed during polysaccharide titrations indicates that interactions occur in the intermediate exchange regime, and analysis of these data allows estimation of affinities and stoichiometries that range from 4 × 104 to 12 × 104 M−1 per site and multiple sites per polysaccharide, respectively. We also found that lactose can still bind to the CRD S-face of GM-bound Gal-3, with the binding of one ligand attenuating affinity of the other. These data are compared with previous results on Gal-1, revealing differences and similarities. They also provide research direction to the development of these polysaccharides as galectin-targeting therapeutics in the clinic.
Ribociclib (KISQALI), a cyclin‐dependent kinase 4/6 inhibitor approved for the first‐line treatment of HR+/HER2– advanced breast cancer with an aromatase inhibitor, is administered with no restrictions on concomitant gastric pH‐elevating agents or food intake. The influence of proton pump inhibitors (PPIs) on ribociclib bioavailability was assessed using 1) biorelevant media solubility, 2) physiologically based pharmacokinetic (PBPK) modeling, 3) noncompartmental analysis (NCA) of clinical trial data, and 4) population PK (PopPK) analysis. This multipronged approach indicated no effect of gastric pH changes on ribociclib PK and served as a platform for supporting ribociclib labeling language, stating no impact of gastric pH‐altering agents on the absorption of ribociclib, without a dedicated drug–drug interaction trial. The bioequivalence of ribociclib exposure with or without a high‐fat meal was demonstrated in a clinical trial. Lack of restrictions on ribociclib dosing may facilitate better patient compliance and therefore clinical benefit.
Objective Enrollment of patients of Black African ancestry with systemic lupus erythematosus (SLE) in phase II and phase III of the belimumab trials was not reflective of the racial distribution observed in the lupus population. This study was undertaken to assess the efficacy and safety of intravenous (IV) belimumab plus standard therapy in patients of self‐identified Black race. Methods EMBRACE (GSK Study BEL115471; ClinicalTrials.gov identifier: NCT01632241) was a 52‐week multicenter, double‐blind, placebo‐controlled trial in adults of self‐identified Black race with active SLE who received monthly belimumab 10 mg/kg IV, or placebo, plus standard therapy. The optional 26‐week open‐label extension phase included patients who completed the double‐blind phase. The primary end point of the study was SLE Responder Index (SRI) response rate at week 52 with modified proteinuria scoring adapted from the SLE Disease Activity Index 2000 (SLEDAI‐2K) (SRI–SLEDAI‐2K). Key secondary end points included SRI response rate at week 52, time to first severe SLE flare, and reductions in prednisone dose. Results The modified intent‐to‐treat population comprised 448 patients, of whom 96.9% were women and the mean ± SD age was 38.8 ± 11.42 years. The primary end point (improvement in the SRI–SLEDAI‐2K response rate at week 52) was not achieved (belimumab 48.7%, placebo 41.6%; odds ratio 1.40 [95% confidence interval 0.93, 2.11], P = 0.1068); however, numerical improvements favoring belimumab were observed, in which the SRI–SLEDAI‐2K response rates were higher in those who received belimumab compared with those who received placebo, especially in patients with SLE who had high disease activity or renal manifestations at baseline. The safety profile of belimumab was generally consistent with that observed in previous SLE trials. Adverse events were the primary reasons for double‐blind phase withdrawals (belimumab 5.4%, placebo 6.7%). Conclusion The primary end point of this study was not achieved, but improvement with belimumab versus placebo was observed, suggesting that belimumab remains a suitable treatment option for SLE management in patients of Black African ancestry.
Abstract Background: In the MONALEESA (ML) trials, addition of ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor) to endocrine therapy (ET) prolonged progression-free survival (PFS) in patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC). RIB was generally well tolerated, with adverse events (AEs) managed effectively by dose modifications. Here we present efficacy data for RIB-based regimens of interest for the proposed indication (i.e. with a non-steroidal aromatase inhibitor [NSAI] or fulvestrant [FUL]) from ML-2, -3, and -7 in pts who received no prior ET for ABC and who had ≥1 RIB dose reduction, to explore the efficacy of RIB in pts who need to dose reduce. Methods: Pts included in this analysis were: postmenopausal women with HR+, HER2– ABC and no prior ET for ABC who received RIB (600 mg; 3-weeks-on/1-week-off) with letrozole (2.5 mg/day; ML-2 [NCT01958021]), or FUL (500 mg per label; ML-3 [NCT02422615]); and premenopausal women with no prior ET and ≤1 line of chemotherapy for ABC who received RIB with an NSAI (anastrozole: 1 mg/day; letrozole: 2.5 mg/day; ML-7 [NCT02278120]) plus goserelin (3.6 mg every 28 days). Dose reductions for RIB (600 to 400 to 200 mg) were permitted. Primary endpoint was PFS. Secondary endpoints included overall response rate (ORR), clinical benefit rate (CBR), and safety. Results: In ML-2, -3, and -7, ≥1 RIB dose reduction occurred (n/N) in 169/334 (51%), 92/238 (39%), and 91/246 (37%) pts assigned to RIB, respectively. AEs were the main reason for dose reduction, with all-grade neutropenia the most common AE leading to dose reduction (ML-2 69%, ML-3 80%, ML-7 82%). Median PFS (months) was prolonged with RIB vs placebo in pts without a RIB dose reduction (ML-2: 27.7 vs 16.0; ML-3: not reached [NR] vs 18.3; ML-7: 23.8 vs 13.8); median PFS in pts with ≥1 RIB dose reduction was: ML-2 25.3, ML-3 NR, and ML-7 27.5 months. In pts with measurable disease and without a RIB dose reduction, ORR was 46% (ML-2), 43% (ML-3), and 48% (ML-7); CBR was 70%, 68%, and 79%, respectively. In pts with measurable disease and ≥1 RIB dose reduction, ORR was 62% (ML-2), 57% (ML-3), and 55% (ML-7); CBR was 88%, 85%, and 88%, respectively. The most common Grade 3/4 AEs in the RIB vs placebo groups (≥5% of pts in either ML trial, irrespective of causality or dose reduction) were neutropenia (ML-2: 62% vs 1%; ML-3: 55% vs 0; ML-7: 65% vs 4%), leukopenia (ML-2: 21% vs 1%; ML-3: 12% vs 0; ML-7: 16% vs 1%), hypertension (ML-2: 13% vs 13%; ML-3: 5% vs 5%; ML-7: 2% vs 3%), increased alanine aminotransferase (ML-2: 10% vs 1%; ML-3: 10% vs 0; ML-7: 5% vs 1%), and increased aspartate aminotransferase (ML-2: 6% vs 1%; ML-3: 6% vs 0; ML-7: 4% vs 1%). Conclusions: Results from the ML-2, -3, and -7 trials suggest that pts who start on 600 mg of RIB and require dose reduction for the management of their AEs, or for other reasons, continue to derive clinical benefit. Citation Format: Beck JT, Neven P, Sohn J, Chan A, Sonke GS, Bachelot T, Campos-Gomez S, Martin M, Bardia A, Alam J, Miller M, Diaz-Padilla I, Kong O, Hart L. Ribociclib treatment benefit in patients with advanced breast cancer with ≥1 dose reduction: Data from the MONALEESA-2, -3, and -7 trials [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-06.
Black patients have an increased prevalence and severity of systemic lupus erythematosus (SLE), alongside higher mortality rates. The efficacy and safety of intravenous (IV) belimumab has been demonstrated in several Phase 2/3 studies; however, the small number of black patients within these trials, and the conflicting results, have limited conclusions regarding efficacy in this population. The objective of this study was to specifically assess the efficacy and safety of IV belimumab plus standard of care (SoC) in black patients with active, auto antibody-positive SLE.
Methods
EMBRACE (NCT01632241) is a randomized, multicenter, double-blind, placebo-controlled trial in patients of self identified black race, aged 18 years, with active SLE at screening. Patients were randomized (2:1) to monthly belimumab 10 mg/kg IV or placebo, plus SoC. The primary endpoint was the SLE Responder Index (SRI) response rate with modified SLEDAI-2K (S2K) scoring for proteinuria at Week 52 (SRI-S2K response required a 4 point reduction in the SELENA-SLEDAI (SS)-S2K, no worsening [increase of <0.3] in Physician's Global Assessment (PGA), and no new BILAG A or 2 new B organ domain scores). Key secondary endpoints included SRI response rate with SS scoring of proteinuria at Week 52, time to first severe SFI flare, and reductions in prednisone dose by 25% to 7.5 mg/day during Weeks 4052. Subgroup analyses of the primary endpoint were also conducted. Step-down sequential testing was utilized to control the overall type 1 error rate (2-sided, alpha=0.05). Safety was assessed by monitoring adverse events (AEs).
Results
The mITT population comprised 448 patients; 96.9% were female and mean (SD) age was 38.8 (11.42) years. Although the study did not achieve the primary endpoint, numerical trends were observed in favor of belimumab, and significant improvements were observed in subgroups with characteristics of high disease activity (HDA; table). Study withdrawals were similar between groups (belimumab 22.4%; placebo 24.2%) and AEs were the primary reason for withdrawals (belimumab 5.4%; placebo 6.7%). The percentage of patients who experienced an AE (belimumab 83.7%; placebo 87.3%) or serious AE (belimumab 10.9%; placebo 18.8%) was similar between groups. Two deaths occurred within the belimumab group (0.6%; pneumonia and meningitis); neither were established as directly related to belimumab.
Conclusions
Whilst the primary endpoint of this study in black patients with SLE was not achieved, improvements in favor of belimumab were observed, with significant benefits in patients with HDA. The safety profile was acceptable and consistent with previous studies.
