AstraZeneca (Switzerland)

An analysis of chemical reactions used in current medicinal chemistry (2014), three decades ago (1984), and in natural product total synthesis has been conducted. The analysis revealed that of the current most frequently used synthetic reactions, none were discovered within the past 20 years and only two in the 1980s and 1990s (Suzuki-Miyaura and Buchwald-Hartwig). This suggests an inherent high bar of impact for new synthetic reactions in drug discovery. The most frequently used reactions were amide bond formation, Suzuki-Miyaura coupling, and SNAr reactions, most likely due to commercial availability of reagents, high chemoselectivity, and a pressure on delivery. We show that these practices result in overpopulation of certain types of molecular shapes to the exclusion of others using simple PMI plots. We hope that these results will help catalyze improvements in integration of new synthetic methodologies as well as new library design.

BACKGROUND: The direct-acting platelet P2Y12 receptor antagonist ticagrelor can reduce the incidence of major adverse cardiovascular events when administered at hospital admission to patients with ST-segment elevation myocardial infarction (STEMI). Whether prehospital administration of ticagrelor can improve coronary reperfusion and the clinical outcome is unknown. METHODS: We conducted an international, multicenter, randomized, double-blind study involving 1862 patients with ongoing STEMI of less than 6 hours' duration, comparing prehospital (in the ambulance) versus in-hospital (in the catheterization laboratory) treatment with ticagrelor. The coprimary end points were the proportion of patients who did not have a 70% or greater resolution of ST-segment elevation before percutaneous coronary intervention (PCI) and the proportion of patients who did not have Thrombolysis in Myocardial Infarction flow grade 3 in the infarct-related artery at initial angiography. Secondary end points included the rates of major adverse cardiovascular events and definite stent thrombosis at 30 days. RESULTS: The median time from randomization to angiography was 48 minutes, and the median time difference between the two treatment strategies was 31 minutes. The two coprimary end points did not differ significantly between the prehospital and in-hospital groups. The absence of ST-segment elevation resolution of 70% or greater after PCI (a secondary end point) was reported for 42.5% and 47.5% of the patients, respectively. The rates of major adverse cardiovascular events did not differ significantly between the two study groups. The rates of definite stent thrombosis were lower in the prehospital group than in the in-hospital group (0% vs. 0.8% in the first 24 hours; 0.2% vs. 1.2% at 30 days). Rates of major bleeding events were low and virtually identical in the two groups, regardless of the bleeding definition used. CONCLUSIONS: Prehospital administration of ticagrelor in patients with acute STEMI appeared to be safe but did not improve pre-PCI coronary reperfusion. (Funded by AstraZeneca; ATLANTIC ClinicalTrials.gov number, NCT01347580.).

Abstract High-throughput experimentation (HTE) has revolutionized the pharmaceutical industry, most notably allowing for rapid screening of compound libraries against therapeutic targets. The past decade has also witnessed the extension of HTE principles toward the realm of small-molecule process chemistry. Today, most major pharmaceutical companies have created dedicated HTE groups within their process development teams, invested in automation technology to accelerate screening, or both. The industry’s commitment to accelerating process development has led to rapid innovations in the HTE space. This review will deliver an overview of the latest best practices currently taking place within our teams in process chemistry by sharing frequently studied transformations, our perspective for the next several years in the field, and manual and automated tools to enable experimentation. A series of case studies are presented to exemplify state-of-the-art workflows developed within our laboratories.

Development of novel therapies for CNS tumors requires reliable assessment of response and progression. This requirement has been particularly challenging in neuro-oncology for which contrast enhancement serves as an imperfect surrogate for tumor volume and is influenced by agents that affect vascular permeability, such as antiangiogenic therapies. In addition, most tumors have a nonenhancing component that can be difficult to accurately quantify. To improve the response assessment in neuro-oncology and to standardize the criteria that are used for different CNS tumors, the Response Assessment in Neuro-Oncology (RANO) working group was established. This multidisciplinary international working group consists of neuro-oncologists, medical oncologists, neuroradiologists, neurosurgeons, radiation oncologists, neuropsychologists, and experts in clinical outcomes assessments, working in collaboration with government and industry to enhance the interpretation of clinical trials. The RANO working group was originally created to update response criteria for high- and low-grade gliomas and to address such issues as pseudoresponse and nonenhancing tumor progression from antiangiogenic therapies, and pseudoprogression from radiochemotherapy. RANO has expanded to include working groups that are focused on other tumors, including brain metastases, leptomeningeal metastases, spine tumors, pediatric brain tumors, and meningiomas, as well as other clinical trial end points, such as clinical outcomes assessments, seizures, corticosteroid use, and positron emission tomography imaging. In an effort to standardize the measurement of neurologic function for clinical assessment, the Neurologic Assessment in Neuro-Oncology scale was drafted. Born out of a workshop conducted by the Jumpstarting Brain Tumor Drug Development Coalition and the US Food and Drug Administration, a standardized brain tumor imaging protocol now exists to reduce variability and improve reliability. Efforts by RANO have been widely accepted and are increasingly being used in neuro-oncology trials, although additional refinements will be needed.

PURPOSE: Nivolumab was assessed in patients with virus-associated tumors in the phase I/II CheckMate 358 trial (ClinicalTrials.gov identifier: NCT02488759). We report on patients with recurrent/metastatic cervical, vaginal, or vulvar cancers. PATIENTS AND METHODS: Patients received nivolumab 240 mg every 2 weeks. Although patients with unknown human papillomavirus status were enrolled, patients known to have human papillomavirus-negative tumors were ineligible. The primary end point was objective response rate. Duration of response (DOR), progression-free survival, and overall survival were secondary end points. Safety and patient-reported outcomes were exploratory end points. RESULTS: Twenty-four patients (cervical, n = 19; vaginal/vulvar, n = 5) were enrolled. Most patients had received prior systemic therapy for metastatic disease (cervical, 78.9%; vaginal/vulvar, 80.0%). Objective response rates were 26.3% (95% CI, 9.1 to 51.2) for cervical cancer and 20.0% (95% CI, 0.5 to 71.6) for vaginal/vulvar cancers. At a median follow-up of 19.2 months, median DOR was not reached (range, 23.3 to 29.5+ months; + indicates a censored observation) in the five responding patients in the cervical cohort; the DOR was 5.0 months in the single responding patient in the vaginal/vulvar cohort. Median overall survival was 21.9 months (95% CI, 15.1 months to not reached) among patients with cervical cancer. Any-grade treatment-related adverse events were reported in 12 of 19 patients (63.2%) in the cervical cohort and all five patients in the vaginal/vulvar cohort; there were no treatment-related deaths. In the cervical cohort, nivolumab treatment generally resulted in stabilization of patient-reported outcomes associated with health status and health-related quality of life. CONCLUSION: The efficacy of nivolumab in patients with recurrent/metastatic cervical and vaginal or vulvar cancers is promising and warrants additional investigation. No new safety signals were identified with nivolumab treatment in this population.

Abstract The ability to track extracellular vesicles (EVs) in vivo without influencing their biodistribution is a key requirement for their successful development as drug delivery vehicles and therapeutic agents. Here, we evaluated the effect of five different optical and nuclear tracers on the in vivo biodistribution of EVs. Expi293F EVs were labeled using either a noncovalent fluorescent dye DiR, or covalent modification with 111indium-DTPA, or bioengineered with fluorescent (mCherry) or bioluminescent (Firefly and NanoLuc luciferase) proteins fused to the EV marker, CD63. To focus specifically on the effect of the tracer, we compared EVs derived from the same cell source and administered systemically by the same route and at equal dose into tumor-bearing BALB/c mice. 111Indium and DiR were the most sensitive tracers for in vivo imaging of EVs, providing the most accurate quantification of vesicle biodistribution by ex vivo imaging of organs and analysis of tissue lysates. Specifically, NanoLuc fused to CD63 altered EV distribution, resulting in high accumulation in the lungs, demonstrating that genetic modification of EVs for tracking purposes may compromise their physiological biodistribution. Blood kinetic analysis revealed that EVs are rapidly cleared from the circulation with a half-life below 10 min. Our study demonstrates that radioactivity is the most accurate EV tracking approach for a complete quantitative biodistribution study including pharmacokinetic profiling. In conclusion, we provide a comprehensive comparison of fluorescent, bioluminescent, and radioactivity approaches, including dual labeling of EVs, to enable accurate spatiotemporal resolution of EV trafficking in mice, an essential step in developing EV therapeutics.

A principal goal of the Mars Science Laboratory (MSL) rover Curiosity is to identify and characterize past habitable environments on Mars. Determination of the mineralogical and chemical composition of Martian rocks and soils constrains their formation and alteration pathways, providing information on climate and habitability through time. The CheMin X-ray diffraction (XRD) and X-ray fluorescence (XRF) instrument on MSL will return accurate mineralogical identifications and quantitative phase abundances for scooped soil samples and drilled rock powders collected at Gale Crater during Curiosity’s 1-Mars-year nominal mission. The instrument has a Co X-ray source and a cooled charge-coupled device (CCD) detector arranged in transmission geometry with the sample. CheMin’s angular range of 5 ∘ to 50 ∘ 2 θ with <0.35 ∘ 2 θ resolution is sufficient to identify and quantify virtually all minerals. CheMin’s XRF requirement was descoped for technical and budgetary reasons. However, X-ray energy discrimination is still required to separate Co K α from Co K β and Fe K α photons. The X-ray energy-dispersive histograms (EDH) returned along with XRD for instrument evaluation should be useful in identifying elements Z >13 that are contained in the sample. The CheMin XRD is equipped with internal chemical and mineralogical standards and 27 reusable sample cells with either Mylar ® or Kapton ® windows to accommodate acidic-to-basic environmental conditions. The CheMin flight model (FM) instrument will be calibrated utilizing analyses of common samples against a demonstration-model (DM) instrument and CheMin-like laboratory instruments. The samples include phyllosilicate and sulfate minerals that are expected at Gale crater on the basis of remote sensing observations.

INTRODUCTION: Chronic kidney disease (CKD) is a progressive disease of growing prevalence, posing serious concerns for global public health. While the economic burden of CKD is substantial, data on the cost of CKD is limited, despite growing pressures on healthcare systems. In this review, we summarise the available evidence in 31 countries and regions and compile a library of costing methodology and estimates of CKD management and disease-associated complications across 31 countries/regions within the Inside CKD programme. METHODS: We collected country/region-specific CKD costs via a pragmatic rapid literature review of local literature and engagement with local experts. We extracted cost data and definitions from identified sources for CKD stages G3a-5, kidney failure with replacement therapy by modality, covering haemodialysis, peritoneal dialysis, and kidney transplants, and disease-associated complications in local currency, converted to United States dollars (USD) and inflated to 2022. RESULTS: Annual direct costs associated with CKD management rose by an average factor of 4 in each country/region upon progression from stage G3a to G5. Mean annual costs per patient increased considerably more from early stages versus dialysis (stage G3a, mean: $3060 versus haemodialysis, mean: $57,334; peritoneal dialysis, mean: $49,490); with estimates for annual costs of transplant also substantially higher (incident: $75,326; subsequent: $16,672). The mean annual per patient costs of complications were $18,294 for myocardial infarction, $8463 for heart failure, $10,168 for stroke and $5975 for acute kidney injury. Costing definitions varied widely in granularity and/or definition across all countries/regions. CONCLUSION: Globally, CKD carries a significant economic burden, which increases substantially with increasing disease severity. We identified significant gaps in published costs and inconsistent costing definitions. Cost-effective interventions that target primary prevention and disease progression are essential to reduce CKD burden. Our results can be used to guide cost collection and facilitate better comparisons across countries/regions to inform healthcare policy.

A concerted commitment across research stakeholders is necessary to increase equity, diversity, and inclusion (EDI) and address barriers to cancer clinical trial recruitment and participation. Racial and ethnic diversity among trial participants is key to understanding intrinsic and extrinsic factors that may affect patient response to cancer treatments. This ASCO and Association of Community Cancer Centers (ACCC) Research Statement presents specific recommendations and strategies for the research community to improve EDI in cancer clinical trials. There are six overarching recommendations: (1) clinical trials are an integral component of high-quality cancer care, and every person with cancer should have the opportunity to participate; (2) trial sponsors and investigators should design and implement trials with a focus on reducing barriers and enhancing EDI, and work with sites to conduct trials in ways that increase participation of under-represented populations; (3) trial sponsors, researchers, and sites should form long-standing partnerships with patients, patient advocacy groups, and community leaders and groups; (4) anyone designing or conducting trials should complete recurring education, training, and evaluation to demonstrate and maintain cross-cultural competencies, mitigation of bias, effective communication, and a commitment to achieving EDI; (5) research stakeholders should invest in programs and policies that increase EDI in trials and in the research workforce; and (6) research stakeholders should collect and publish aggregate data on racial and ethnic diversity of trial participants when reporting results of trials, programs, and interventions to increase EDI. The recommendations are intended to serve as a guide for the research community to improve participation rates among people from racial and ethnic minority populations historically under-represented in cancer clinical trials. ASCO and ACCC will work at all levels to advance the recommendations in this publication.

Animal models are effective for assessing tumor localization of nanosystems but difficult to use for studying penetration beyond the vasculature. Here, we have used well-characterized HCT116 colorectal cancer spheroids to study the effect of nanoparticle (NP) physicochemical properties on penetration and uptake. Incubation of spheroids with Hoechst 33342 resulted in a dye gradient, which facilitated discrimination between the populations of cells in the core and at the periphery of spheroids by flow cytometry. This approach was used to compare doxorubicin and liposomal doxorubicin (Caelyx) and a range of model poly(styrene) nanoparticles of different sizes (30 nm, 50 nm, 100 nm) and with different surface chemistries (50 nm uniform plain, carboxylated, aminated and a range of NPs and polyethylene glycol modified NPs prepared from a promising new functionalized biodegradable polymer (poly(glycerol-adipate), PGA). Unmodified poly(styrene) nanoparticles (30 nm/50 nm) were able to penetrate to the core of HCT116 spheroids more efficiently than larger poly(styrene) nanoparticles (100 nm). Surprisingly, penetration of 30 and 50 nm particles was as good as clinically relevant doxorubicin concentrations. However, penetration was reduced with higher surface charge. PGA NPs of 100 nm showed similar penetration into spheroids as 50 nm poly(styrene) nanoparticles, which may be related to polymer flexibility. PEG surface modification of polymeric particles significantly improved penetration into the spheroid core. The new model combining the use of spheroids Hoechst staining and flow cytometry was a useful model for assessing NP penetration and gives useful insights into the effects of NPs' physical properties when designing nanomedicines.

OBJECTIVE: To evaluate the safety and tolerability of multiple intravenous (IV) doses of sifalimumab in adults with moderate-to-severe systemic lupus erythematosus (SLE). METHODS: In this multicenter, double-blind, placebo-controlled, sequential dose-escalation study, patients were randomized 3:1 to receive IV sifalimumab (0.3, 1.0, 3.0, or 10.0 mg/kg) or placebo every 2 weeks to week 26, then followed up for 24 weeks. Safety assessment included recording of treatment-emergent adverse events (AEs) and serious AEs. Pharmacokinetics, immunogenicity, and pharmacodynamics were evaluated, and disease activity was assessed. RESULTS: Of 161 patients, 121 received sifalimumab (26 received 0.3 mg/kg; 25, 1.0 mg/kg; 27, 3.0 mg/kg; and 43, 10 mg/kg) and 40 received placebo. Patients were predominantly female (95.7%). At baseline, patients had moderate-to-severe disease activity (mean SLE Disease Activity Index score 11.0), and most (75.2%) had a high type I interferon (IFN) gene signature. In the sifalimumab group versus the placebo group, the incidence of ≥1 treatment-emergent AE was 92.6% versus 95.0%, ≥1 serious AE was 22.3% versus 27.5%, and ≥1 infection was 67.8% versus 62.5%; discontinuations due to AEs occurred in 9.1% versus 7.5%, and death occurred in 3.3% (n=4) versus 2.5% (n=1). Serum sifalimumab concentrations increased in a linear and dose-proportional manner. Inhibition of the type I IFN gene signature was sustained during treatment in patients with a high baseline signature. No statistically significant differences in clinical activity (SLEDAI and British Isles Lupus Assessment Group score) between sifalimumab and placebo were observed. However, when adjusted for excess burst steroids, SLEDAI change from baseline showed a positive trend over time. A trend toward normal complement C3 or C4 level at week 26 was seen in the sifalimumab groups compared with baseline. CONCLUSION: The observed safety/tolerability and clinical activity profile of sifalimumab support its continued clinical development for SLE.

AIMS: To examine the manifestation of cardiovascular or renal disease (CVRD) in patients with type 2 diabetes (T2D) initially free from CVRD as well as the mortality risks associated with these diseases. METHODS: Patients free from CVRD were identified from healthcare records in England, Germany, Japan, the Netherlands, Norway and Sweden at a fixed date. CVRD manifestation was defined by first diagnosis of cardiorenal disease, or a stroke, myocardial infarction (MI) or peripheral artery disease (PAD) event. The mortality risk associated with single CVRD history of heart failure (HF), chronic kidney disease (CKD), MI, stroke or PAD was compared with that associated with CVRD-free status. RESULTS: Of 1 177 896 patients with T2D, 772 336 (66%) were CVRD-free and followed for a mean of 4.5 years. A total of 137 081 patients (18%) developed a first CVRD manifestation, represented by CKD (36%), HF (24%), stroke (16%), MI (14%) and PAD (10%). HF or CKD was associated with increased cardiovascular and all-cause mortality risk: hazard ratio (HR) 2.02 (95% confidence interval [CI] 1.75-2.33) and HR 2.05 (95% CI 1.82-2.32), respectively. HF and CKD were separately associated with significantly increased mortality risks, and the combination was associated with the highest cardiovascular and all-cause mortality risk: HRs 3.91 (95% CI 3.02-5.07) and 3.14 (95% CI 2.90-3.40), respectively. CONCLUSION: In a large multinational study of >750 000 CVRD-free patients with T2D, HF and CKD were consistently the most frequent first cardiovascular disease manifestations and were also associated with increased mortality risks. These novel findings show these cardiorenal diseases to be important and serious complications requiring improved preventive strategies.

BACKGROUND: The aims of this study were to: (i) report the baseline characteristics of patients enrolled in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial, (ii) compare DAPA-HF patients to participants in contemporary heart failure (HF) registries and in other recent HF trials, and (iii) compare individuals with diabetes, pre-diabetes and a normal glycated haemoglobin (HbA1c) in DAPA-HF. METHODS AND RESULTS: Adults with HF in New York Heart Association functional class ≥ II, a left ventricular ejection fraction ≤ 40%, an elevated N-terminal pro-B-type natriuretic peptide concentration and receiving standard treatment were eligible for DAPA-HF, which is comparing dapagliflozin 10 mg once daily to matching placebo. In patients without a history of diabetes, previously undiagnosed diabetes was defined as a confirmed HbA1c ≥ 6.5%. Among patients without known or undiagnosed diabetes, pre-diabetes was defined as a HbA1c ≥ 5.7% The remainder of patients, with a HbA1c < 5.7%, were defined as normoglycaemic. Of the 4744 patients (mean age 66 years; 23% women) randomized, 42% had known diabetes and 3% undiagnosed diabetes. Of the remainder, 67% had pre-diabetes and 33% normal HbA1c. Overall, DAPA-HF patients were generally similar to those in recent registries and in relevant trials and had high levels of background therapy: 94% angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, 96% beta-blocker, and 71% mineralocorticoid receptor antagonist; 26% had a defibrillator. Patients with diabetes had worse HF status, more co-morbidity, and greater renal impairment but received similar HF therapy. Patients with diabetes received non-insulin hypoglycaemic therapy alone in 49%, insulin alone in 11%, both in 14%, and none in 26%. CONCLUSIONS: Patients randomized in DAPA-HF were similar to those in other contemporary HF with reduced ejection fraction (HFrEF) registries and trials. These patients were receiving recommended HFrEF therapy and those with diabetes were also treated with conventional glucose-lowering therapy. Consequently, DAPA-HF will test the incremental efficacy and safety of dapagliflozin in HFrEF patients with and without diabetes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03036124.

Abstract Trastuzumab deruxtecan (T-DXd) intracranial activity has been observed in small or retrospective patient cohorts with human epidermal growth factor receptor 2–positive (HER2 + ) advanced/metastatic breast cancer (mBC) and stable or active (untreated/previously treated and progressing) brain metastases (BMs). The phase 3b/4 DESTINY-Breast12 study investigated T-DXd in patients with HER2 + mBC and is, to our knowledge, the largest prospective study of T-DXd in patients with BMs in this setting. Patients (stable/active BMs ( n = 263) and no BMs ( n = 241)) treated with one or more prior anti-HER2–based regimens received T-DXd (5.4 mg per kg). Primary endpoints were progression-free survival (PFS; BMs cohort) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (non-BMs cohort). Additional endpoints included central nervous system (CNS) PFS, ORR, time to second progression, CNS ORR (BMs cohort), incidence of new symptomatic CNS metastases (non-BMs cohort), time to progression, duration of response, overall survival and safety (both cohorts). No formal hypothesis testing was conducted for this single-arm, open-label study. In the BMs cohort, 12-month PFS was 61.6% (95% confidence interval (CI): 54.9–67.6), and 12-month CNS PFS was 58.9% (95% CI: 51.9–65.3). In the non-BMs cohort, ORR was 62.7% (95% CI: 56.5–68.8). Grade 3 or higher adverse events occurred in 51% (BMs cohort) and 49% (non-BMs cohort) of patients. Investigator-reported interstitial lung disease/pneumonitis occurred in 16% (grade ≥3: 3%) of patients with BMs and 13% (grade ≥3: 1%) of patients without BMs. These data show substantial and durable overall and intracranial activity for T-DXd, supporting its use in previously treated patients with HER2 + mBC irrespective of stable/active baseline BMs. ClinicalTrials.gov identifier: NCT04739761 .

Background Immune checkpoint blockade (ICB) promotes adaptive immunity and tumor regression in some cancer patients. However, in patients with immunologically “cold” tumors, tumor-resident innate immune cell activation may be required to prime an adaptive immune response and so exploit the full potential of ICB. Whilst Toll-like receptor (TLR) agonists have been used topically to successfully treat some superficial skin tumors, systemic TLR agonists have not been well-tolerated. Methods The response of human immune cells to TLR7 and 8 agonism was measured in primary human immune cell assays. MEDI9197 (3M-052) was designed as a novel lipophilic TLR7/8 agonist that is retained at the injection site, limiting systemic exposure. Retention of the TLR7/8 agonist at the site of injection was demonstrated using quantitative whole-body autoradiography, HPLC-UV, and MALDI mass spectrometry imaging. Pharmacodynamic changes on T cells from TLR7/8 agonist treated B16-OVA tumors was assessed by histology, quantitative real time PCR, and flow cytometry. Combination activity of TLR7/8 agonism with immunotherapies was assessed in vitro by human DC-T cell MLR assay, and in vivo using multiple syngeneic mouse tumor models. Results Targeting both TLR7 and 8 triggers an innate and adaptive immune response in primary human immune cells, exemplified by secretion of IFNα, IL-12 and IFNγ. In contrast, a STING or a TLR9 agonist primarily induces release of IFNα. We demonstrate that the TLR7/8 agonist, MEDI9197, is retained at the sight of injection with limited systemic exposure. This localized TLR7/8 agonism leads to Th1 polarization, enrichment and activation of natural killer (NK) and CD8+ T cells, and inhibition of tumor growth in multiple syngeneic models. The anti-tumor activity of this TLR7/8 agonist is enhanced when combined with T cell-targeted immunotherapies in pre-clinical models. Conclusion Localized TLR7/8 agonism can enhance recruitment and activation of immune cells in tumors and polarize anti-tumor immunity towards a Th1 response. Moreover, we demonstrate that the anti-tumor effects of this TLR7/8 agonist can be enhanced through combination with checkpoint inhibitors and co-stimulatory agonists.

An iron-tetraphenylcyclopentadienone tricarbonyl complex is demonstrated to act as a precursor of a catalyst for the formation of C-N bonds through a "hydrogen-borrowing" reaction between amines and alcohols.

UNLABELLED: The influence of pretreatment bone turnover on alendronate efficacy is not known. In the FIT, we examined the effect of pretreatment bone turnover on the antifracture efficacy of daily alendronate given to postmenopausal women. The nonspine fracture efficacy of alendronate was significantly greater among both osteoporotic and nonosteoporotic women with higher baseline levels of the bone formation marker PINP. INTRODUCTION: Previous trials have shown that high bone turnover is associated with greater increases in BMD among bisphosphonate-treated women. The influence of pretreatment bone turnover levels on antifracture efficacy has not been well studied. MATERIALS AND METHODS: We randomized women 55-80 years of age with femoral neck BMD T scores < or = -1.6 to alendronate (ALN), 5-10 mg/day (n = 3105), or placebo (PBO; n = 3081). At baseline, 3495 women were osteoporotic (femoral neck BMD T score < or = -2.5 or prevalent vertebral fracture), and 2689 were not osteoporotic (BMD T score > -2.5 and no prevalent vertebral fracture). Pretreatment levels of bone-specific alkaline phosphatase (BSALP), N-terminal propeptide of type 1 collagen (PINP), and C-terminal cross-linked telopeptide of type 1 collagen (sCTx) were measured in all participants using archived serum (20% fasting). The risk of incident spine and nonspine fracture was compared in ALN- and PBO-treated subjects stratified into tertiles of baseline bone marker level. RESULTS AND CONCLUSIONS: During a mean follow-up of 3.2 years, 492 nonspine and 294 morphometric vertebral fractures were documented. Compared with placebo, the reduction in nonspine fractures with ALN treatment differed significantly among those with low, intermediate, and high pretreatment levels of PINP levels (p = 0.03 for trend). For example, among osteoporotic women in the lowest tertile of pretreatment PINP (<41.6 ng/ml), the ALN versus PBO relative hazard for nonspine fracture was 0.88 (95% CI: 0.65, 1.21) compared with a relative hazard of 0.54 (95% CI: 0.39, 0.74) among those in the highest tertile of PINP (>56.8 ng/ml). Results were similar among women without osteoporosis at baseline. Although they did not reach statistical significance, similar trends were observed with baseline levels of BSALP. Conversely, spine fracture treatment efficacy among osteoporotic women did not differ significantly according to pretreatment marker levels. Spine fracture treatment efficacy among nonosteoporotic women was related to baseline BSALP (p = 0.05 for trend). In summary, alendronate nonspine fracture efficacy is greater among both osteoporotic and nonosteoporotic women with high pretreatment PINP. If confirmed in other studies, these findings suggest that bisphosphonate treatment may be most effective in women with elevated bone turnover.

Abstract The clinical benefit of PD-1 blockade can be improved by combination with CTLA4 inhibition but is commensurate with significant immune-related adverse events suboptimally limiting the doses of anti-CTLA4 mAb that can be used. MEDI5752 is a monovalent bispecific antibody designed to suppress the PD-1 pathway and provide modulated CTLA4 inhibition favoring enhanced blockade on PD-1+ activated T cells. We show that MEDI5752 preferentially saturates CTLA4 on PD-1+ T cells versus PD-1− T cells, reducing the dose required to elicit IL2 secretion. Unlike conventional PD-1/CTLA4 mAbs, MEDI5752 leads to the rapid internalization and degradation of PD-1. Moreover, we show that MEDI5752 preferentially localizes and accumulates in tumors providing enhanced activity when compared with a combination of mAbs targeting PD-1 and CTLA4 in vivo. Following treatment with MEDI5752, robust partial responses were observed in two patients with advanced solid tumors. MEDI5752 represents a novel immunotherapy engineered to preferentially inhibit CTLA4 on PD-1+ T cells. Significance: The unique characteristics of MEDI5752 represent a novel immunotherapy engineered to direct CTLA4 inhibition to PD-1+ T cells with the potential for differentiated activity when compared with current conventional mAb combination strategies targeting PD-1 and CTLA4. This molecule therefore represents a step forward in the rational design of cancer immunotherapy. See related commentary by Burton and Tawbi, p. 1008. This article is highlighted in the In This Issue feature, p. 995

Abstract Background Although 6 COVID-19 vaccines have been approved by the World Health Organisation as of 16 th June 2021, global supply remains limited. An understanding of the immune response associated with protection could facilitate rapid licensure of new vaccines. Methods Data from a randomised efficacy trial of ChAdOx1 nCoV-19 (AZD1222) vaccine in the UK was analysed to determine the antibody levels associated with protection against SARS-CoV-2. Anti-spike and anti-RBD IgG by multiplex immunoassay, pseudovirus and live neutralising antibody at 28 days after the second dose were measured in infected and non-infected vaccine recipients. Weighted generalised additive models for binary data were applied to symptomatic and asymptomatic SARS-CoV-2 infection data from ChAdOx1 nCoV-19 recipients. Cubic spline smoothed log antibody levels, and weights were applied to account for potential selection bias in sample processing. Models were adjusted for baseline risk of exposure to SARS-CoV-2 infection. Results Higher levels of all immune markers were correlated with a reduced risk of symptomatic infection. Vaccine efficacy of 80% against primary symptomatic COVID-19 was achieved with an antibody level of 40923 (95% CI: 16748, 125017) and 63383 (95% CI: 16903, not computed (NC)) for anti-spike and anti-RBD, and 185 (95% CI: NC, NC) and 247 (95% CI: 101, NC) for pseudo- and live-neutralisation assays respectively. Antibody responses did not correlate with overall protection against asymptomatic infection. Conclusions Correlates of protection can be used to bridge to new populations using validated assays. The data can be used to extrapolate efficacy estimates for new vaccines where large efficacy trials cannot be conducted. More work is needed to assess correlates for emerging variants.

BACKGROUND: The impact of gastro-oesophageal reflux disease on work productivity has become increasingly important, as the symptoms of gastro-oesophageal reflux disease affect individuals in their productive years of life. AIMS: To assess the impact of gastro-oesophageal reflux disease on reduced work productivity and to identify the predictors of reduced productivity. METHODS: A sample of employed individuals reporting chronic heartburn was selected from US household mail survey respondents. Heartburn severity and frequency were recorded using a diary, and work productivity was assessed using the Work Productivity and Activity Impairment Questionnaire for Patients with Symptoms of Gastro-oesophageal Reflux Disease. Predictors of reduced productivity were evaluated. RESULTS: Over 30% of heartburn sufferers reported reduced productivity. Individuals with symptoms of gastro-oesophageal reflux disease (n = 1003) reported 6.0% reduced productivity attributable to symptoms. Over 48% of respondents with severe symptoms reported reduced productivity, compared with 40% and 12% of respondents with moderate and mild symptoms, respectively. Using logistic regression, severity, a younger age and nocturnal symptoms were associated with increased odds of reduced productivity. In those reporting nocturnal heartburn, medication use and sleep interference increased the odds of reduced productivity. CONCLUSIONS: Reduced work productivity is seen in a large proportion of subjects on prescription medication for gastro-oesophageal reflux disease. Symptom severity and nocturnal heartburn are significantly associated with reduced work productivity, particularly when nocturnal heartburn interferes with sleep.