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There is an unmet need for COVID-19 prevention in patient populations who have not mounted or are not expected to mount an adequate immune response to complete COVID-19 vaccination. We previously reported that a single subcutaneous 1200 mg dose of the monoclonal antibody combination casirivimab and imdevimab (CAS + IMD) prevented symptomatic SARS-CoV-2 infections by 81·4% in generally healthy household contacts of SARS-CoV-2-infected individuals over a 1-month efficacy assessment period. Here we present additional results, including the 7-month follow-up period (months 2-8), providing additional insights about the potential for efficacy in pre-exposure prophylaxis settings.This was a randomised, double-blind, placebo-controlled trial done in the USA, Romania, and Moldova in 2020-2021, before the emergence of omicron (B.1.1.529) and omicron-lineage variants. Uninfected and unvaccinated household contacts of infected individuals, judged by the investigator to be in good health, were randomly assigned (1:1) to receive 1200 mg CAS + IMD or placebo by subcutaneous injection according to a central randomisation scheme provided by an interactive web response system; randomisation was stratified per site by the test results of a local diagnostic assay for SARS-CoV-2 and age group at baseline. COVID-19 vaccines were prohibited before randomisation, but participants were allowed to receive COVID-19 vaccination during the follow-up period. Participants who developed COVID-19 symptoms during the follow-up period underwent RT-PCR testing. Prespecified endpoints included the proportion of previously uninfected and baseline-seronegative participants (seronegative-modified full analysis set) who had RT-PCR-confirmed COVID-19 in the follow-up period (post-hoc for the timepoints of months 2-5 and 6-8 only) and underwent seroconversion (ie, became seropositive, considered a proxy for any SARS-CoV-2 infections [symptomatic and asymptomatic]; prespecified up to day 57, post-hoc for all timepoints thereafter). We also assessed the incidence of treatment-emergent adverse events. This study is registered with ClinicalTrials.gov, NCT04452318.From July 13, 2020, to Oct 4, 2021, 2317 participants who were RT-PCR-negative for SARS-CoV-2 were randomly assigned, of whom 1683 (841 assigned to CAS + IMD and 842 assigned to placebo) were seronegative at baseline. During the entirety of the 8-month study, CAS + IMD reduced the risk of COVID-19 by 81·2% (nominal plt;0·0001) versus placebo (prespecified analysis). During the 7-month follow-up period, protection was greatest during months 2-5, with a 100% relative risk reduction in COVID-19 (nominal plt;0·0001; post-hoc analysis). Efficacy waned during months 6-8 (post-hoc analysis). Seroconversion occurred in 38 (4·5%) of 841 participants in the CAS + IMD group and in 181 (21·5%) of 842 in the placebo group during the 8-month study (79·0% relative risk reduction vs placebo; nominal plt;0·0001). Six participants in the placebo group were hospitalised due to COVID-19 versus none who received CAS + IMD. Serious treatment-emergent adverse events (including COVID-19) were reported in 24 (1·7%) of 1439 participants receiving CAS + IMD and in 23 (1·6%) of 1428 receiving placebo. Five deaths were reported, none of which were due to COVID-19 or related to the study drugs.CAS + IMD is not authorised in any US region as of Jan 24, 2022, because data show that CAS + IMD is not active against omicron-lineage variants. In this study, done before the emergence of omicron-lineage variants, a single subcutaneous 1200 mg dose of CAS + IMD protected against COVID-19 for up to 5 months of community exposure to susceptible strains of SARS-CoV-2 in the pre-exposure prophylaxis setting, in addition to the post-exposure prophylaxis setting that was previously shown.Regeneron Pharmaceuticals, F Hoffmann-La Roche, US National Institute of Allergy and Infectious Diseases, US National Institutes of Health.

Background Randomized controlled trials evaluated monoclonal antibodies for the treatment (Study 2067) and prevention (Study 2069) of COVID-19. Household contacts of the infected index case in Study 2067 were enrolled in Study 2069 and prospectively followed; these cohorts provided a unique opportunity to evaluate correlates of transmission, specifically viral load. Methods This post-hoc analysis was designed to identify and evaluate correlates of SARS-CoV-2 transmission, adjusting for potential confounding factors related to source SARS-CoV-2 viral load and risk of SARS-CoV-2 acquisition in this population. Correlates of transmission were evaluated in potential transmission pairs (any infected household member plus susceptible household contact). Results In total, 943 participants were included. In multivariable regression, two potential correlates were determined to have a statistically significant (P Conclusions In this prospective, post-hoc analysis that controlled for confounders, the two key correlates for transmission of SARS-CoV-2 within a household are sharing a bedroom and increased viral load, consistent with increased exposure to the infected individual.

BackgroundFibrodysplasia ossificans progressiva (FOP), an ultra-rare disorder caused by mutations in the gene encoding activin A receptor type 1 (ACVR1), is characterized by painful flare-ups and cumulative heterotopic ossification (HO). Garetosmab, a fully-human monoclonal antibody blocking activin A, prevents HO in FOP mice.MethodsLUMINA-1 (NCT03188666) was a phase 2, multi-center, randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, and effects on HO of intravenous (IV) garetosmab 10 mg/kg every 4 weeks (Q4W). Adult patients with FOP were randomized to garetosmab or placebo for 28 weeks (Period_1), followed by an open-label period (Period_2). After Period_2, patients were allowed to stay on garetosmab in an open-label extension. For Period_1, primary endpoints were HO total lesion activity (HO-TLA) by18F-sodium fluoride positron emission tomography (18F-NaF PET) and HO total lesion volume by computed tomography (CT). The Period_2 primary endpoint compared the number of new lesions in Period_2 versus Period_1. The safety primary endpoint was incidence and severity of TEAEs through the end of the Period 1 at week 28.FindingsPatients (n=44) were randomized to garetosmab (n=20) or placebo (n=24). In Period_1, there was a trend for garetosmab to decrease HO-TLA versus placebo (24.6%;P=0.07), primarily driven by near complete prevention of new lesions (97% decrease by18F-NaF PET, post-hocP=0.009; 90% relative reduction by CT, post-hocP=0.017); flare-ups were significantly reduced (P=0.0005). For placebo patients transitioning to garetosmab in Period_2, no patients developed new HO lesions (0% in Period_2 versus 40.9% in Period_1;P=0.0027) by CT. All 44 patients met primary safety endpoint of at least one TEAE during Period 1. Garetosmab was associated with more adverse events than placebo: mild recurrent epistaxis, madarosis, and skin/soft tissue infections. Overall, the AEs were predominantly mild in severity, with no effect on patients’ ability to receive garetosmab. Five deaths (5/44; 11.4%) occurred either in Period_2 or the open-label extension. The deaths were associated with baseline disease severity in some, preexisting comorbidities in others and occurred following 8-16 doses (median: 15) of garetosmab in the open label/follow-up periods.InterpretationGaretosmab reduced flare-ups and prevented new HO lesions in FOP patients. Although side effects were mild to moderate, there were a relatively high number of deaths for a small study; the deaths were not related to epistaxis and considered unlikely to be related to garetosmab.FundingRegeneron Pharmaceuticals, Inc.

Aims: To describe the real-world economic burden of patients with anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) treated with post-crizotinib, second-line ALK inhibit...

IMPORTANCE: Easy-to-administer anti–SARS-CoV-2 treatments may be used to prevent progression from asymptomatic infection to symptomatic disease and to reduce viral carriage. OBJECTIVE: To evaluate the effect of combination subcutaneous casirivimab and imdevimab on progression from early asymptomatic SARS-CoV-2 infection to symptomatic COVID-19. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled, phase 3 trial of close household contacts of a SARS-CoV-2–infected index case at 112 sites in the US, Romania, and Moldova enrolled July 13, 2020–January 28, 2021; follow-up ended March 11, 2021. Asymptomatic individuals (aged ≥12 years) were eligible if identified within 96 hours of index case positive test collection. Results from 314 individuals positive on SARS-CoV-2 reverse transcriptase–quantitative polymerase chain reaction (RT-qPCR) testing are reported. INTERVENTIONS: Individuals were randomized 1:1 to receive 1 dose of subcutaneous casirivimab and imdevimab, 1200 mg (600 mg of each; n = 158), or placebo (n = 156). MAIN OUTCOMES AND MEASURES: The primary end point was the proportion of seronegative participants who developed symptomatic COVID-19 during the 28-day efficacy assessment period. The key secondary efficacy end points were the number of weeks of symptomatic SARS-CoV-2 infection and the number of weeks of high viral load (>4 log(10) copies/mL). RESULTS: Among 314 randomized participants (mean age, 41.0 years; 51.6% women), 310 (99.7%) completed the efficacy assessment period; 204 were asymptomatic and seronegative at baseline and included in the primary efficacy analysis. Subcutaneous casirivimab and imdevimab, 1200 mg, significantly prevented progression to symptomatic disease (29/100 [29.0%] vs 44/104 [42.3%] with placebo; odds ratio, 0.54 [95% CI, 0.30-0.97]; P = .04; absolute risk difference, −13.3% [95% CI, −26.3% to −0.3%]). Casirivimab and imdevimab reduced the number of symptomatic weeks per 1000 participants (895.7 weeks vs 1637.4 weeks with placebo; P = .03), an approximately 5.6-day reduction in symptom duration per symptomatic participant. Treatment with casirivimab and imdevimab also reduced the number of high viral load weeks per 1000 participants (489.8 weeks vs 811.9 weeks with placebo; P = .001). The proportion of participants receiving casirivimab and imdevimab who had 1 or more treatment-emergent adverse event was 33.5% vs 48.1% for placebo, including events related (25.8% vs 39.7%) or not related (11.0% vs 16.0%) to COVID-19. CONCLUSIONS AND RELEVANCE: Among asymptomatic SARS-CoV-2 RT-qPCR–positive individuals living with an infected household contact, treatment with subcutaneous casirivimab and imdevimab antibody combination vs placebo significantly reduced the incidence of symptomatic COVID-19 over 28 days. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04452318

Objectives This observational study identified attributes of patient-reported satisfaction with therapy for multiple myeloma (MM), described the treatment-related time burden and indirect costs, and investigated the effect of administration route (oral vs. injectable) on these outcomes among patients with newly diagnosed MM (NDMM) and among caregivers. Methods Patients residing in the USA with a self-reported diagnosis of NDMM were recruited from PatientsLikeMe, MyelomaCrowd, and Facebook (16 December 2016 and 6 July 2017) to complete an electronic survey including questions on treatment experience, economic burden, and standardized patient-reported outcome measures, including the Treatment Satisfaction Questionnaire for Medication with three domains (global satisfaction, effectiveness, and convenience) and the Work Productivity and Activity Impairment Questionnaire. Univariate and multivariate analyses identified predictors of patient-perceived treatment satisfaction. Results Among 188 patients, worse Eastern Cooperative Oncology Group performance status (ECOG PS) was correlated with lower patient-perceived effectiveness and convenience of their current treatment. White race and oral administration route were independently correlated with higher patient-perceived convenience of treatment. Injectable therapy use was associated with a trend towards increased activity impairment (43 vs. 34%; p = 0.05) and significantly higher time burden of treatment administration, with threefold higher adjusted indirect costs of MM therapy compared with solely orally administered therapies (monthly mean $US482 vs. 153; 2016 values; p

Background REGEN-COV (previously known as REGN-COV2), a combination of the monoclonal antibodies casirivimab and imdevimab, has been shown to markedly reduce the risk of hospitalization or death among high-risk persons with coronavirus disease 2019 (Covid-19). Whether subcutaneous REGEN-COV prevents severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and subsequent Covid-19 in persons at high risk for infection because of household exposure to a person with SARS-CoV-2 infection is unknown. Methods We randomly assigned, in a 1:1 ratio, participants (≥12 years of age) who were enrolled within 96 hours after a household contact received a diagnosis of SARS-CoV-2 infection to receive a total dose of 1200 mg of REGEN-COV or matching placebo administered by means of subcutaneous injection. At the time of randomization, participants were stratified according to the results of the local diagnostic assay for SARS-CoV-2 and according to age. The primary efficacy end point was the development of symptomatic SARS-CoV-2 infection through day 28 in participants who did not have SARS-COV-2 infection (as measured by reverse-transcriptase–quantitative polymerase-chain-reaction assay) or previous immunity (seronegativity). Results Symptomatic SARS-CoV-2 infection developed in 11 of 753 participants in the REGEN-COV group (1.5%) and in 59 of 752 participants in the placebo group (7.8%) (relative risk reduction [1 minus the relative risk], 81.4%; P104 copies per milliliter) was shorter (0.4 weeks and 1.3 weeks, respectively). No dose-limiting toxic effects of REGEN-COV were noted. Conclusions Subcutaneous REGEN-COV prevented symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection in previously uninfected household contacts of infected persons. Among the participants who became infected, REGEN-COV reduced the duration of symptomatic disease and the duration of a high viral load. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04452318.)

ImportanceEasy-to-administer antiviral treatments may be used to prevent progression from asymptomatic infection to COVID-19 and to reduce viral carriage.ObjectiveEvaluate the efficacy and safety of subcutaneous casirivimab and imdevimab antibody combination (REGEN-COV) to prevent progression from early asymptomatic SARS-CoV-2 infection to COVID-19.DesignRandomized, double-blind, placebo-controlled, phase 3 study that enrolled asymptomatic close contacts living with a SARS-CoV-2–infected household member (index case). Participants who were SARS-CoV-2 RT-qPCR–positive at baseline were included in the analysis reported here.SettingMulticenter trial conducted at 112 sites in the United States, Romania, and Moldova.ParticipantsAsymptomatic individuals ≥12 years of age were eligible if identified within 96 hours of collection of the index case’s positive SARS-CoV-2 test sample.InterventionsA total of 314 asymptomatic, SARS-CoV-2 RT-qPCR–positive individuals living with an infected household contact were randomized 1:1 to receive a single dose of subcutaneous REGEN-COV 1200mg (n=158) or placebo (n=156).Main Outcome(s) and Measure(s)The primary endpoint was the proportion of participants who developed symptomatic COVID-19 during the 28-day efficacy assessment period. The key secondary efficacy endpoints were the number of weeks of symptomatic SARS-CoV-2 infection and the number of weeks of high viral load (>4 log10 copies/mL). Safety was assessed in all treated participants.ResultsSubcutaneous REGEN-COV 1200mg significantly prevented progression from asymptomatic to symptomatic disease compared with placebo (31.5% relative risk reduction; 29/100 [29.0%] vs 44/104 [42.3%], respectively; P=.0380). REGEN-COV reduced the overall population burden of high–viral load weeks (39.7% reduction vs placebo; 48 vs 82 total weeks; P=.0010) and of symptomatic weeks (45.3% reduction vs placebo; 89.6 vs 170.3 total weeks; P=.0273), the latter corresponding to an approximately 5.6-day reduction in symptom duration per symptomatic participant. Six placebo-treated participants had a COVID-19–related hospitalization or ER visit versus none for those receiving REGEN-COV. The proportion of participants receiving placebo who had ≥1 treatment-emergent adverse events was 48.1% compared with 33.5% for those receiving REGEN-COV, including events related (39.7% vs 25.8%, respectively) or not related (16.0% vs 11.0%, respectively) to COVID-19.Conclusions and RelevanceSubcutaneous REGEN-COV 1200mg prevented progression from asymptomatic SARS-CoV-2 infection to COVID-19, reduced the duration of high viral load and symptoms, and was well tolerated.Trial RegistrationClinicalTrials.gov Identifier, NCT04452318KEY POINTSQuestionCan treatment with the anti–SARS-CoV-2 antibody combination REGEN-COV prevent COVID-19 and reduce viral load when given to recently exposed and asymptomatic individuals?FindingsIn this randomized, double-blind, phase 3 trial, subcutaneously administered REGEN-COV 1200 mg significantly reduced progression of asymptomatic SARS-CoV-2 infection to symptomatic infection (ie, COVID-19) by 31.5% compared with placebo. REGEN-COV also reduced the overall population burden of high viral load weeks (39.7% reduction vs placebo; 48 vs 82 total weeks; P=.0010).MeaningIn the current pandemic, utilization of subcutaneous REGEN-COV prevents progression of early asymptomatic infection to COVID-19 and reduces viral carriage.

Background In a Phase 3 prevention trial, the monoclonal antibody combination casirivimab and imdevimab (REGEN-COVTM) administered subcutaneously (SC) prevented symptomatic SARS-CoV-2 infection in asymptomatic adults/adolescents living in the same household as a SARS-CoV-2-infected individual (index case). Individuals with cardiovascular disease (CVD) and/or diabetes are at increased risk of moderate/severe COVID-19. Methods Uninfected individuals ≥12 years, identified ≤96 hours of index case being diagnosed SARS-CoV-2 positive, were randomized 1:1 to REGEN-COV 1200mg SC or placebo. The primary endpoint was the proportion of participants who developed symptomatic infection (COVID-19) during the 28-day efficacy assessment period among those who were SARS-CoV-2 RT-qPCR negative and without evidence of immunity (seronegative) at baseline. A post-hoc analysis assessed efficacy in participants with CVD (including hypertension) and/or diabetes. Overall safety is reported. Results The study included SARS-CoV-2 RT-qPCR negative participants at baseline (n=2067). There was an 81.4% relative risk reduction (RRR) of symptomatic infection with REGEN-COV in the overall seronegative population (n=1505; Figure 1; Table 1). In participants with CVD (n=332) or diabetes (n=103), the RRRs of developing symptomatic infection with REGEN-COV versus placebo were 54.9% and 69.0%, respectively. Similar results were observed when analyses were performed regardless of baseline serology status. Treatment-emergent adverse events occurring at ≥2% included COVID-19, asymptomatic COVID-19, headache, and injection-site reaction (Table 2). Conclusions In study participants with CVD and/or diabetes, who are known to be at increased risk of severe disease if infected, treatment with REGEN-COV SC reduced the risk of developing symptomatic SARS-CoV-2 infection, consistent with the overall study results..

The poly(para-dioxanone) (PPDO) was blended with various contents of poly(lactic-co-glycolic acid) (PLGA) (10wt%, 20wt%, 30wt%) by solution co-precipitation in this study. The advantage of PLGA is derived from its safety and low cost. The hydrolytic degradation of PPDO / PLGA blends in vitro was studied by weight loss, water absorption, thermal properties, surface morphology, and mechanical properties in phosphate-buffered saline (pH = 7.44) at 37 ℃ for 8 weeks. After degradation, the weight loss and water absorption of all blends increased significantly. PPDO/PLGA (70/30) showed the largest weight loss during the whole degradation period. With the prolongation of hydrolysis degradation time, higher crystallinity of the PPDO was attributed to the chain breakage of unstable ester bonds. A fenestral structure with defects was formed on the surface of the blend bars with degradation. Besides, the glass transition temperature (Tg), the melting temperature (Tm), tensile strength, and breaking elongation of the blends decreased with the hydrolysis rate varying with the blend composition. Compared with pure PLGA and pure PPDO, the PPDO/PLGA blends exhibited a higher hydrolysis rate because of poor miscibility. Therefore, PPDO/PLGA blends with tailored degradation times have a lot of potential as a biomaterial for biomedical applications, such as high-performance absorbable sutures or a filler for ameliorating facial wrinkles.

Aim: To assess time-to-treatment discontinuation (TTD) of brigatinib following treatment with ALK tyrosine kinase inhibitor(s) (TKIs) in patients with ALK-positive (ALK+) non-small-cell lung cancer (NSCLC) receiving brigatinib through the international early access program. Patients & analysis: Analysis was performed for patients with ALK+ NSCLC treated with prior ALK TKIs, including next-generation ALK TKIs. Results: Data for 604 patients (21 countries), including patients with prior next-generation ALK TKIs, were reported. The median TTD of brigatinib in patients with prior crizotinib, alectinib, ceritinib or lorlatinib was 10.0, 8.7, 10.3 and 7.5 months, respectively. Conclusion: Brigatinib appears to be effective and tolerable in real-world clinical practice regardless of prior treatment with first or NG ALK TKIs.

Background: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, autosomal dominant disorder driven by mutations in ACVR1 that render it responsive to Activin A. FOP is characterized by progressive heterotopic ossification (HO) and distressing inflammatory events called “flare-ups.” Flare-ups can precede new HO; however, limited prospective data exists on this phenomenon. Garetosmab (GAR), an investigational human monoclonal antibody against Activin A, blocks formation of new HO in FOP. Methods: This is a post-hoc analysis of LUMINA-1 (NCT03188666) a phase 2, randomized, double-blind, placebo-controlled study, which evaluated the safety and efficacy of GAR (10 mg/kg/week IV) versus placebo (PBO) in adult patients with FOP over 28 weeks. Patient-reported flare-ups were collected via a patient diary and severity level was reported as mild, moderate or severe. Clinician-reported flare-ups were collected as adverse events in the trial. HO lesions were imaged by 18F-NaF positron emission tomography (PET) and whole-body low-dose X-ray computed tomography (CT). Results: There was a two-fold higher proportion of patients who reported one or more flare-ups on PBO 17/24 (71%) compared with GAR 7/20 (35%). Clinicians reported a four-fold higher proportion of patients experiencing one or more flare-ups on PBO 10/24 (42%) compared with GAR 2/20 (10%). Overall rates of flare-up events were two-fold higher on PBO vs. GAR (1.4 vs. 0.65 events/patient/28 weeks) for patient-reported events and eight-fold higher on PBO vs. GAR by clinician report (0.83 vs. 0.10 events/patient/28 weeks). Most flare-ups occurred on the extremities and back; pain was the most commonly reported symptom. Patient-reported flare-ups on PBO were more frequently reported as severe (29.4%) compared with GAR (7.7%). Among subjects with at least 12 weeks of follow-up from start of patient-reported flare-up, development of new HO near the site was 5/27 (18.5%) on PBO and (0%) on GAR. Of all new HO lesions, 41% on PBO and 0% on GAR occurred with spatial and temporal relation to flare-up. Conclusions: Approximately two-thirds of patients on PBO reported flare-ups over 28 weeks. GAR was associated with reductions in frequency and severity of flare-ups. Fewer than 20% of patient-reported flare-ups were associated with new HO, indicating frequent discordance of these phenomena, and compatible with previous reports. GAR’s ability to reduce patient- and clinician-reported flare-ups, as well as new HO lesions may provide an important therapeutic option.

Summary Group testing, where individuals are tested initially in pools, is widely used to screen a large number of individuals for rare diseases. Triggered by the recent development of assays that detect multiple infections at once, screening programs now involve testing individuals in pools for multiple infections simultaneously. Tebbs, McMahan, and Bilder (2013, Biometrics) recently evaluated the performance of a two-stage hierarchical algorithm used to screen for chlamydia and gonorrhea as part of the Infertility Prevention Project in the United States. In this article, we generalize this work to accommodate a larger number of stages. To derive the operating characteristics of higher-stage hierarchical algorithms with more than one infection, we view the pool decoding process as a time-inhomogeneous, finite-state Markov chain. Taking this conceptualization enables us to derive closed-form expressions for the expected number of tests and classification accuracy rates in terms of transition probability matrices. When applied to chlamydia and gonorrhea testing data from four states (Region X of the United States Department of Health and Human Services), higher-stage hierarchical algorithms provide, on average, an estimated 11% reduction in the number of tests when compared to two-stage algorithms. For applications with rarer infections, we show theoretically that this percentage reduction can be much larger.

Diversity partitioning is becoming widely used to decompose the total number of species recorded in an area or region $$(\gamma )$$ into the average number of species within samples $$(\alpha )$$ and the average difference in species composition $$(\beta )$$ among samples. Single-value metrics of $$\alpha $$ and $$\beta $$ diversity are popular because they may be applied at multiple scales and because of their ease in computation and interpretation. Studies thus far, however, have emphasized observed diversity components or comparisons to randomized, null distributions. In addition, prediction of $$\alpha $$ and $$\beta $$ components using environmental or spatial variables has been limited to more extensive data sets because multiple samples are required to estimate single $$\alpha $$ and $$\beta $$ components. Lastly, observed diversity components do not incorporate variation in detection probabilities among species or samples. In this study, we used hierarchical Bayesian models of species abundances to provide predictions of $$\alpha $$ and $$\beta $$ components in species richness and composition using environmental and spatial variables. We illustrate our approach using butterfly data collected from 26 grassland remnants to predict spatially nested patterns of $$\alpha $$ and $$\beta $$ based on the predicted counts of butterflies. Diversity partitioning using a Bayesian hierarchical model incorporated variation in detection probabilities by butterfly species and habitat patches, and provided prediction intervals for $$\alpha $$ and $$\beta $$ components using environmental and spatial variables.

Background Treatment advances in the last 10 years, especially the wide use of IMiDs and PI based combinations, have greatly improved the outcomes of patients with multiple myeloma (MM). To understand better the performance of available combination of IMiDs and PIs in the real-world setting, we performed secondary data analyses of two observational studies: FlatIron (Miksad, Clin Pharm Ther, 2018) and Multiple Myeloma Research Foundation (MMRF) CoMMpass study (Miller, Blood Cancer J, 2017). In addition, the MMRF dataset provides patients baseline gene expression and mutation profiles, allowing us to investigate potential correlations between certain biomarkers and drug side-effects. Methods We selected NDMM pts who received VRd or KRd as the first line treatment: 1952 pts for VRd and 43 for KRd in Flatiron as of April 30, 2018; while 297 pts for VRd and 63 for KRd in CoMMpass (with patient ID limited to earlier than MMRF_2700 to exclude a subgroup of new patients with limited follow-up). The Flatiron pts were mostly from community hospitals while CoMMpass pts from academic centers, thus these data sets were analyzed separately. Duration of treatment (DOT, a frequently used proxy for PFS in observational studies) was used to evaluate drug treatment effects. DOT was estimated using Kaplan Meier method. Difference between survival curves was tested for statistical significance using the two-sided log-rank test. In addition, differentially expressed genes were identified for MMRF patients by comparing baseline gene expression between responders (VGPR or better) and sub-optimal-responders (PR + SD + PD) patient sub-groups, for KRd and VRd, respectively. Any gene with a t.test p-value < 0.05 and fold-change > 2 between the two groups is considered as a differentially expressed gene. These genes were subsequently evaluated through pathway and Open Targets analysis. Results Analysis of the Flatiron dataset showed that baseline characteristics were comparable between patients treated with KRd and VRd (age, gender, race, median BSA, ECOG, hemoglobin, platelets, creatinine clearance, albumin, ISS stages, and beta2-macroglobulin). Similarly, in the MMRF dataset the baseline characteristics were comparable between KRd and VRd pts except for age (median age at 62 for VRd vs 59 for KRd, p-value = 0.00013), creatinine (median at 88.4 µmol/L for VRd vs 78.7 µmol/L for KRd, p-value = 0.03) and hemoglobin (median at 6.76 mmol/L for VRd vs 7.32 mmol/L for KRd, p-value = 0.0018). Analysis of the Flatiron dataset showed a median DOT (Figure A) with VRd of 16.81 months (95% CI: 15.69, 19.11) and 11.12 months (95% CI: 8.06, 29.21) with KRd. A comparison of the two treatments show a hazard Ratio (HR, 95% CI, p-value) for VRd vs KRd are: HR = 0.75, CI = (0.49, 1.14), p-value = 0.18. A similar observation was done using the MMRF dataset (Figure A). Here the median DOT for VRd was 39 months (95% CI: 32, 47) while for KRd was 21 months (95% CI: 15, NA) months. The hazard ratio for VRd vs KRd was: HR = 0.61, (95% CI: 0.41, 0.90), p-value = 0.01. Taken together these observations suggests that in real world the benefits gained by VRd treatment are larger than KRd treatment in NDMM patients. Although both bortezomib and carfilzomib are proteasome inhibitors, they are chemically different and while bortezomib is a reversible inhibitor, carfilzomib is not. To investigate the molecular characteristics of the responder and sub-optimal-responders treated with these two therapies, we used the baseline gene expression profiles from the MMRF dataset to identify VRd or KRd sensitivity related genes: 97 and 283 genes were identified as differentially expressed genes between drug-responder and sub-optimal-responder groups for VRd and KRd, respectively (Figure B). Pathway and Open Targets analysis were performed on these genes to generate hypotheses for the molecular bases for drug sensitivity as well as observed adverse events such as cardiac side-effects (results will be presented at ASH). Conclusions From two observational studies, it appears that VRd leads to longer DOT than KRd in the first line treatment for NDMM patients. Also, drug sensitivity related genes were identified which would help better understand differential efficacy and side-effects. A key limitation of this analysis is the smaller number for KRd pts due to more recent carfilzomib approvals, and longer follow up is needed to confirm these observations. Figure. Figure. Disclosures Li: Takeda Pharmaceuticals International Co.: Employment. Ren:Takeda Pharmaceuticals International Co.: Employment. Shen:Takeda Pharmaceuticals International Co.: Employment. Hou:Takeda Pharmaceuticals International Co.,: Employment. Su:Takeda Pharmaceuticals International Co.,: Employment. Di Bacco:Takeda Pharmaceuticals International Co.: Employment. Hong:Takeda Pharmaceuticals International Co.,: Employment. Galaznik:Takeda Pharmaceuticals International Co.: Employment. Dash:Takeda Pharmaceuticals International Co.: Employment. Crossland:Takeda Pharmaceuticals International Co.: Employment. Dolin:Takeda Pharmaceuticals International Co.: Employment; Shire: Other: PD holds shares in Shire ; GSK: Other: PD holds shares in GSK. Szalma:Takeda Pharmaceuticals International Co.,: Employment; Johnson and Johnson: Other: share holder.

13 Background: De-novo brain metastases (BM) occur in 15-35% of patients with ALK+ NSCLC, and the prevalence increases to as high as 60% over the course of first-line crizotinib therapy. Reports on the economic burden of brain metastases in patients who progress on first-line therapy are scarce. The objective of this study was to evaluate the economic impact of BM among patients with ALK+ NSCLC treated with second-line ALK inhibitors. Methods: This retrospective study used the Optum Research database to identify adult patients with a lung cancer diagnosis code (≥1 inpatient claim or ≥2 outpatient claims ≥30 days but ≤1 year apart) and use of a second-line ALK inhibitor (e.g. alectinib or ceritinib) after crizotinib, between January 2011 and March 2017. Index date was defined as the date of the first claim with a second-line ALK inhibitor. BM were identified if the patient had BM diagnosis prior to index date. Healthcare costs and resource utilization were calculated on a per-patient-per-month (PPPM) basis up to 12 months of follow up after index date. Multivariate regression was used to assess the impact of BM on PPPM cost, while controlling for patient demographics, comorbidities and type of second-line ALK inhibitor. Results: 523 patients with NSCLC received at least one ALK inhibitor during the study period. Use of a second-line ALK inhibitor (alectinib or ceritinib post-crizotinib) was observed in 112 patients (43 alectinib, 69 ceritinib). Among second-line ALK inhibitor users, 52.7% (n = 59) had BM. In those with BM, the PPPM total healthcare costs were $26,415 compared with $21,278 in those without BM. Regression results showed that the adjusted mean total PPPM cost for those receiving second-line ALK inhibitor with BM was 1.39 times as high as those without BM (p-value = 0.0287). Conclusions: Economic burden of brain metastases is high for ALK+ NSCLC patients receiving second-line ALK inhibitors. The study highlights the economic value of novel therapies to delay brain metastases during early lines of therapy in these patients.