Janssen Biotech, Inc.

The DNA damage response (DDR) protein DNA Polymerase θ (Polθ) is synthetic lethal with homologous recombination (HR) factors and is therefore a promising drug target in BRCA1/2 mutant cancers. We discover an allosteric Polθ inhibitor (Polθi) class with 4–6 nM IC50 that selectively kills HR-deficient cells and acts synergistically with PARP inhibitors (PARPi) in multiple genetic backgrounds. X-ray crystallography and biochemistry reveal that Polθi selectively inhibits Polθ polymerase (Polθ-pol) in the closed conformation on B-form DNA/DNA via an induced fit mechanism. In contrast, Polθi fails to inhibit Polθ-pol catalytic activity on A-form DNA/RNA in which the enzyme binds in the open configuration. Remarkably, Polθi binding to the Polθ-pol:DNA/DNA closed complex traps the polymerase on DNA for more than forty minutes which elucidates the inhibitory mechanism of action. These data reveal a unique small-molecule DNA polymerase:DNA trapping mechanism that induces synthetic lethality in HR-deficient cells and potentiates the activity of PARPi.

316 Background: Apa-RP is a multicenter, open-label, single-arm Phase 2 study of adjuvant treatment with apalutamide and androgen deprivation therapy (ADT) in treatment-naïve patients with high-risk localized prostate cancer who underwent radical prostatectomy (NCT04523207). A rash management guide was implemented to improve dermatologic adverse events (AEs) that included proactive patient education on appropriate skin care and monitoring for rash, and frequent outreach through patient phone calls. We present rash-related safety data from Apa-RP compared with data from 2 Phase 3 apalutamide registrational studies. Methods: 108 patients were treated with apalutamide 240 mg once daily with ADT for 12 28-day cycles. Rash occurrence was monitored and skin-related AEs were defined by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grading scale. These factors were collated and compared with data from the North American population from SPARTAN (non-metastatic castration-resistant prostate cancer; NCT01946204) and TITAN (metastatic castration-sensitive prostate cancer; NCT02489318). Results: Of 108 patients in Apa-RP, 21.3% developed rash vs 28.3% in SPARTAN and 33.3% in TITAN. Information on rash severity, median time to onset of first rash, the proportion of patients with rash resolution, median time to resolution and the treatment administered for rash are provided in the Table. Conclusions: The Apa-RP rash management protocol demonstrates a proactive and patient-empowered approach to monitoring and managing patients on apalutamide who develop skin rash. With increased vigilance from the care team and appropriate patient education, it may be possible to reduce the incidence, severity and median time to resolution of skin rash. Clinical trial information: NCT04523207 . [Table: see text]

Simple Summary The administration of chimeric antigen receptor (CAR)-T cell therapies in an outpatient setting is expanding; however, there is limited evidence comparing outcomes from outpatient and inpatient administration. This research aims to compare the clinical and economic outcomes associated with the administration of CAR-T therapies in either setting for patients with hematological cancer, by summarizing existing evidence, and also to test the hypothesis that outpatient administration of CAR-T therapies yields comparable clinical effectiveness as inpatient treatment while offering significant cost reduction and lower humanistic burden. Abstract Although chimeric antigen receptor (CAR)-T cell therapies are typically administered in the inpatient setting, outpatient administration is rapidly expanding. However, there is limited summarized evidence comparing outcomes between outpatient and inpatient administration. This systematic literature review aims to compare the safety, efficacy, quality of life (QoL), costs, and healthcare resource utilization (HCRU) outcomes in patients with hematological cancer who are administered CAR-T therapy in an outpatient versus an inpatient setting. Publications (2016 or later) that reported the outcomes of interest in patients treated with a CAR-T therapy in both outpatient and inpatient settings, or only the outpatient setting, were reviewed. In total, 38 publications based on 21 studies were included. Safety findings suggested the comparable frequency of adverse events in the two settings. Eleven studies that reported data in both settings showed comparable response rates (80–82% in outpatient and 72–80% in inpatient). Improvements in the QoL were observed in both settings while costs associated with CAR-T therapy were lower in the outpatient setting. Although unplanned hospitalizations were higher in the outpatient cohort, overall HCRU was lower. Outpatient administration of CAR-T therapy appears to have comparable outcomes in safety, efficacy, and QoL to inpatient administration while reducing the economic burden.

Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1 A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics. Many genetic factors that contribute to uterine leiomyomata (UL) - the most common tumours of the female genital tract - remain to be discovered. Here, the authors conduct a UL meta-genome-wide association study, and find loci related to altered muscle tissue biology that are associated with UL.

Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10–11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants. Genome-wide association studies of individuals from an isolated population (data from the Finnish biobank study FinnGen) and consequent meta-analyses facilitate the identification of previously unknown coding variant associations for both rare and common diseases.

B-cell maturation antigen (BCMA)-targeting therapies, including bispecific antibodies (BsAbs) and antibody-drug conjugates (ADC), are promising treatments for multiple myeloma (MM), but disease may progress after their use. CARTITUDE-2 is a phase 2, multicohort study evaluating the safety and efficacy of cilta-cel, an anti-BCMA chimeric antigen receptor T therapy, in various myeloma patient populations. Patients in cohort C progressed despite treatment with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and non‑cellular anti-BCMA immunotherapy. A single cilta-cel infusion was given after lymphodepletion. The primary end point was minimal residual disease (MRD) negativity at 10−5. Overall, 20 patients were treated (13 ADC-exposed; 7 BsAb-exposed; 1 in the ADC group also had prior BsAb exposure); 16 (80%) were refractory to prior anti-BCMA therapy. At a median follow-up of 11.3 months (range, 0.6-16.0), 7/20 (35%) patients were MRD-negative (7/10 [70.0%] in the MRD-evaluable subset). Overall response rate (95% CI) was 60.0% (36.1-80.9). Median duration of response and progression-free survival (95% CI) were 11.5 (7.9-not estimable) and 9.1 (1.5-not estimable) months, respectively. The most common adverse events were hematologic. Cytokine release syndrome occurred in 12 (60%) patients (all grade 1/2); 4 had immune effector cell-associated neurotoxicity syndrome (2 grade 3/4); none had parkinsonism. Seven (35%) patients died (3 of progressive disease, 4 of adverse events [1 treatment-related, 3 unrelated]). Cilta-cel induced favorable responses in patients with relapsed/refractory MM and prior exposure to anti-BCMA treatment who have exhausted other therapies. This trial was registered at www.clinicaltrials.gov as #NCT04133636.

Cardiovascular diseases are the leading cause of premature death and disability worldwide, with both genetic and environmental determinants. While genome-wide association studies have identified multiple genetic loci associated with cardiovascular diseases, exact genes driving these associations remain mostly uncovered. Due to Finland’s population history, many deleterious and high-impact variants are enriched in the Finnish population giving a possibility to find genetic associations for protein-truncating variants that likely tie the association to a gene and that would not be detected elsewhere. In a large Finnish biobank study FinnGen, we identified an association between an inframe insertion rs534125149 in MFGE8 (encoding lactadherin) and protection against coronary atherosclerosis. This variant is highly enriched in Finland, and the protective association was replicated in meta-analysis of BioBank Japan and Estonian biobank. Additionally, we identified a protective association between splice acceptor variant rs201988637 in MFGE8 and coronary atherosclerosis, independent of the rs534125149, with no significant risk-increasing associations. This variant was also associated with lower pulse pressure, pointing towards a function of MFGE8 in arterial aging also in humans in addition to previous evidence in mice. In conclusion, our results suggest that inhibiting the production of lactadherin could lower the risk for coronary heart disease substantially. A genome-wide association study identifies MFGE8 as protective against coronary atherosclerosis in European and East Asian populations.

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele. Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

Over the last decade, cancer immunotherapy has progressed from an academically interesting field to one of the most promising forms of new treatments in which not the cancer but the immune system is treated. In particular, genetic modification for purposeful redirection of autologous T cells is providing hope to many treatment-resistant patients. This personalized form of medicine is radically different from more traditional oncologic drugs. With these evolving medical advancements and more cellular therapies becoming available, some regulatory agencies have created new regulatory requirements to manage the production of these types of products. The regulations are specifically suited for the manufacture of gene and cell therapy products, as they use a risk-based approach towards product development and manufacturing, when there is limited characterization available. The correct interpretation of how and when requirements apply is crucial, since theoretical approaches to implementing GMP can easily lead to disproportionate and unwarranted restrictions that may not address the specific risks that regulators were intending to control. This is especially relevant for cell collection and biopreservation preceding the manufacturing process for products manufactured from autologous T cells. Both the fresh and cryopreserved apheresis materials can be filed as minimally manipulated starting materials to the authorities. The preservation of such cellular material can then routinely be managed using the available regulations for tissues and cells, allowing for a more fit-for-purpose approach to the control measures implemented.

Large-scale biobank initiatives and commercial repositories store genomic data collected from millions of individuals, and tools to leverage the rapidly growing pool of health and genomic data in disease prevention are needed. Here, we describe the derivation and validation of genomics-enhanced risk tools for two common cardiometabolic diseases, coronary heart disease and type 2 diabetes. Data used for our analyses include the FinnGen study (N = 309,154) and the UK Biobank project (N = 343,672). The risk tools integrate contemporary genome-wide polygenic risk scores with simple questionnaire-based risk factors, including demographic, lifestyle, medication, and comorbidity data, enabling risk calculation across resources where genome data is available. Compared to routinely used clinical risk scores for coronary heart disease and type 2 diabetes prevention, the risk tools show at least equivalent risk discrimination, improved risk reclassification (overall net reclassification improvements ranging from 3.7 [95% CI 2.8–4.6] up to 6.2 [4.6–7.8]), and capacity to be improved even further with standard lipid and blood pressure measurements. Without the need for blood tests or evaluation by a health professional, the risk tools provide a powerful yet simple method for preliminary cardiometabolic risk assessment for individuals with genome data available. Max Tamlander et al. combine polygenic risk scores and clinical assessments to improve prediction of coronary artery disease and type 2 diabetes in European cohorts. Taken together, their results provide a useful method for preliminary cardiometabolic risk assessment in patients.

Introduction: Cytokine release syndrome (CRS) is a common toxicity associated with chimeric antigen receptor (CAR) T-cell therapies. Corticosteroids and steroid-sparing therapies such as tocilizumab, an interleukin-6 receptor antagonist, and anakinra, an interleukin-1 receptor antagonist, have been used to reduce the incidence and severity of these toxicities. Preclinical and clinical case studies of anakinra, administered subcutaneously or intravenously at various doses, have shown promising results in the management of CRS and systemic inflammatory responses resembling hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS). In CARTITUDE-1, CRS occurred in 95% of heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM) receiving ciltacabtagene autoleucel (cilta-cel), a CAR T-cell therapy with 2 B-cell maturation antigen-targeting single-domain antibodies (Berdeja et al. Lancet 2021). Per protocol, tocilizumab was required to manage CRS with option to give steroids and/or anakinra per investigator discretion. Here, we report the institutional experiences of anakinra use in the management of CRS in patients who have received cilta-cel as part of the CARTITUDE-1 study. Methods: Eligible patients had MM and received ≥3 prior therapies or were refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), and had received a PI, IMiD, and anti-CD38 antibody (Berdeja et al. Lancet 2021). After apheresis, bridging therapy was permitted. Patients received a single cilta-cel infusion (target dose: 0.75×10 6 CAR+ viable T cells/kg; range 0.5-1.0×10 6) 5-7 days after lymphodepletion (300 mg/m 2 cyclophosphamide, 30 mg/m 2 fludarabine daily for 3 days). Lee et al (Blood 2014) grading criteria for CRS were mapped to the ASTCT criteria for CRS. Post-hoc analysis of data revealed use of anakinra at some sites in patients who failed to respond to the initial management of CRS with tocilizumab +/- dexamethasone or in clinical settings where rise of ferritin and/or liver function tests were indicative for continued HLH/MAS-like manifestations (Kennedy et al. ASH 2020). Results: Of 97 patients in CARTITUDE-1, CRS occurred in 92 (95%) patients; 4% were grade 3/4. The median time to onset was 7 days (range 1-12) and median duration was 4 days (range 1-14). Supportive measures to treat CRS were administered to 91% of patients, most commonly tocilizumab (69%; 4 patients received ≥3 doses), corticosteroids (22%), and anakinra (18 patients, 19%). CRS resolved in 99% of patients. Anakinra was administered after initial tocilizumab and within the first 48 hours (range 0-6 days) of CRS onset for the majority of patients as part of effective management of CRS. Anakinra was administered at a dose of 100-200 mg every 8-12 hours over a median of 2.5 days (range 1-15 days). CRS uniformly resolved following anakinra use in CARTITUDE-1, apart from one patient who died from sepsis (grade 5 outcome) due to HLH/MAS considered related to treatment (Table). Conclusions: CRS events in cilta-cel-treated patients in CARTITUDE-1 were common, generally low-grade, and successfully managed with standard tocilizumab +/- dexamethasone. The use of anakinra should be considered in patients with persistent CRS/inflammatory symptoms despite tocilizumab use, and in particular in patients with HLH/MAS-like symptoms/phenotype occurring following CRS or in the absence of prior CRS. Figure 1 Figure 1. Disclosures Wong: Amgen: Consultancy; Genentech: Research Funding; Fortis: Research Funding; Janssen: Research Funding; GloxoSmithKlein: Research Funding; Dren Biosciences: Consultancy; Caelum: Research Funding; BMS: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Richard: Karyopharm, Janssen: Honoraria. Lin: Juno: Consultancy; Legend: Consultancy; Merck: Research Funding; Bluebird Bio: Consultancy, Research Funding; Sorrento: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Research Funding; Gamida Cell: Consultancy; Vineti: Consultancy. Madduri: Janssen: Current Employment. Jackson: Janssen: Current Employment; Memorial Sloan Kettering Cancer Center: Consultancy. Zudaire: Janssen: Current Employment. Romanov: Janssen: Current Employment. Trigg: Janssen: Current Employment. Vogel: Janssen Global Services, LLC: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Garrett: Legend Biotech USA: Current Employment. Nesheiwat: Legend Biotech USA: Current Employment. Martin: Oncopeptides: Consultancy; Sanofi: Research Funding; Janssen: Research Funding; GlaxoSmithKline: Consultancy; Amgen: Research Funding. Jagannath: Bristol Myers Squibb: Consultancy; Legend Biotech: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Takeda: Consultancy; Sanofi: Consultancy. OffLabel Disclosure At the time of abstract submission, cilta-cel is being investigated for the treatment of multiple myeloma but is not yet approved

Background Amyloid light-chain (AL) amyloidosis is a rare disease with poor survival and significant morbidity. Limited information on the treatment patterns, healthcare resource utilization (HCRU) and clinical outcomes of Canadian AL amyloidosis patients is currently available. This study analyzed existing administrative claims data to better understand this patient population in the real-world setting. Methods Population-based administrative databases in Alberta, Canada were queried from 2010 to 2019 using a claims-based algorithm to identify potential cases of systemic AL amyloidosis. The medical charts of individuals flagged by the algorithm were subsequently reviewed by a trained clinician to confirm the diagnosis. Baseline characteristics, sequencing of pharmacologic therapies, overall survival (OS), and HCRU were evaluated. Individuals with AL amyloidosis were matched 1:4 with members of the general population based on age and sex. The mean difference in number of healthcare touch points was then estimated. HCRU was assessed starting from the time of diagnosis for individuals with AL amyloidosis and starting from the date of first encounter with the healthcare system within the corresponding calendar year for matched members of the general population. Robust variance estimation was used to address clustering due to matching. Results A total of 215 patients were confirmed to have AL amyloidosis. At baseline, the mean age at diagnosis was 66 years (range: 25 to 93 years). The majority of patients were men (59.5%), had an Eastern Cooperative Oncology Group (ECOG) performance status between 0-1 (60.9%), and had at least one comorbidity (84.7%). Approximately 1 in 3 patients had a concurrent multiple myeloma diagnosis. Renal and cardiac involvement were more common at baseline (67.9% and 55.8%, respectively) than liver involvement (15.3%). CyBorD was given to 66.4% of patients who initiated pharmacologic therapy, while most of the remaining 33.6% of patients received another bortezomib-based combination therapy. The most common 2L therapy was the combination of lenalidomide and dexamethasone which was given to 29.9% of individuals who initiated 2L. Median OS from initiation of 1L was markedly improved in patients diagnosed between 2012-2019 compared to 2010-2011 (63.4 vs. 34.5 months, respectively; log-rank p=0.07). Relative to age-sex matched members of the general population, individuals with AL amyloidosis had 118.7 more encounters with the healthcare system within the follow-up period (robust 95% CI: 79.4 to 157.9). Conclusions Since 2012, CyBorD has been the standard of care for Canadian AL amyloidosis patients. While survival has increased over time, 5-year survival remains low which highlights an unmet need for more effective therapies. Relative to the general population, individuals with AL amyloidosis had significantly higher HCRU, underscoring the high disease burden.

Background & Aims CD4⁺ T cells are regulated by activating and inhibitory cues and dysregulation of these proper regulatory inputs predisposes to aberrant inflammation and exacerbation of disease. We investigated the role of the inhibitory receptor, paired immunoglobulin-like receptor B (PIR-B) in the regulation of the CD4⁺ T-cell inflammatory response and exacerbation of the colitic phenotype. Methods We employed Il10-/- spontaneous and CD4⁺CD45RBhi T cell transfer models of colitis with PIR-B (Pirb-/-) deficient mice. Flow cytometry, western blot, RNA-seq analysis was performed on wild type and Pirb-/- CD4⁺ T cells. In silico analyses were performed on RNA-seq dataset of ileal biopsy samples from pediatric CD and non-IBD patients and sorted human memory CD4⁺ T cells. Results We identified PIR-B expression on memory CD4⁺ IL-17a⁺ cells. We show that PIR-B regulates CD4⁺ Th17-dependent chronic intestinal inflammatory responses and development of colitis. Mechanistically, we reveal that the PIR-B-SHP-1/2 axis tempers mTORC1 signaling and mTORC1-dependent Caspase-3/7 apoptosis resulting in CD4⁺ IL-17a⁺ cell survival. In silico analyses reveal enrichment of transcriptional signatures for Th17 cells (RORC, RORA, IL-17A) and tissue resident memory (TRM) (HOBIT, IL7R and BLIMP1) networks in PIR-B⁺ murine CD4⁺ T cells and human CD4⁺ T cells that express the human homologue, LILRB3. High levels of LILRB3 expression were strongly associated with mucosal injury and a proinflammatory Th17-signature, and this signature was restricted to a treatment-naïve severe pediatric CD population. Conclusions Our findings demonstrate an intrinsic role for PIR-B/LILRB3 in the regulation of CD4⁺ IL-17a⁺ T cell pathogenic memory responses.

Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15–1.36; P = 1.8 × 10⁻⁷), including sepsis (HR 2.68; 95% CI = 2.25–3.19; P = 3.1 × 10⁻²⁸), pneumonia (HR 1.76; 95% CI = 1.53–2.03; P = 2.3 × 10⁻¹⁵), digestive system infections (HR 1.51; 95% CI = 1.32–1.73; P = 2.2 × 10⁻⁹) and genitourinary infections (HR 1.25; 95% CI = 1.11–1.41; P = 3.7 × 10⁻⁴). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.

e18852 Background: Transferring financial risk from payers to providers to align incentives is central to value-based payment (VBP) reform, including Medicare’s Oncology Care Model (OCM). We simulated the impact of selected cancer- and patient-level factors on providers’ risk in OCM for multiple myeloma (MM), due to its clinical complexity. We hypothesize that risk exposure is sensitive to factors extrinsic to the OCM methodology, including clinical phenotype, disease state and progression rate. Methods: Simulation was used to address omitted variable bias in payer data. We developed 9 key clinical MM scenarios to examine provider risk, based on conceptual frameworks that included patient- and cancer-level factors. The model was parameterized using the Medicare limited data set, research literature and domain knowledge. Twenty factors were varied for each model, e.g. age, autologous stem cell transplant (ASCT). Results: Simulations results showed MM risk for providers depended highly on cancer and patient level factors (see table). For example, high-risk patients were on average $21.5K over target while undergoing ASCT (despite risk adjustment for ASCT) and $18-28K under target for follow on maintenance (maint.) episodes. Conclusions: Provider exposure to risk in OCM is highly sensitive to factors at the cancer and patient level. The distribution of clinical phenotypes, state of disease, and rate of disease progression can significantly impact risk exposure for providers in OCM. New methodologies that model risk in more clinically granular ways are needed to improve VBP in oncology. [Table: see text]

Background: Improving adherence to direct oral anticoagulants (DOAC) is challenging, and simple text messaging reminders have not been effective. Methods: SmartADHERE was a randomized trial that tested a personalized digital and human direct oral anticoagulant adherence intervention compared to usual care. Eligibility required age ≥ 18, newly-prescribed (≤ 90 days) rivaroxaban for atrial fibrillation (AF), 1 of 4 at-risk criteria for nonadherence, and a smartphone. The intervention consisted of combination of a medication management smartphone app, daily app-based reminders, adaptive text messaging, and phone-based counseling for severe nonadherence. The primary outcome was the proportion of days covered by rivaroxaban (PDC) at 6 months. There were 25 U.S. sites, all cardiology and electrophysiology outpatient practices, activated for a target sample size of 378, but the study was terminated by the sponsor prior to reaching target enrollment. Results: There were 139 participants (age 65±9.6 years, 30% female, median CHA2DS2-VASc score 3 with IQR 2-4, mean total medication burden 7.7±4.4). DOAC adherence was high in both arms with no difference in the primary outcome (PDC 0.86±0.25 intervention vs 0.88±0.25 control, p=0.62) or in secondary outcomes including PDC ≥ 0.80 and medication persistence. Per protocol analyses had similar results. Because of the high overall PDC, the likelihood to answer the primary hypothesis was only 51% even if target enrollment were achieved. There were no study-related adverse events. Conclusions: The use of a centralized digital and human adherence intervention was feasible across multiple sites. Overall adherence was much higher than expected despite pre-screening for at-risk individuals. SmartADHERE illustrates the challenges of trials of behavioral and technology interventions, where enrollment itself may lead to selection bias or treatment effects. Pragmatic study designs, such as cluster randomization or stepped-wedge implementation, should be considered to improve enrollment and generalizability.

TRPV4 channels expressed on pulmonary endothelial cells are activated by elevated pulmonary vascular pressure, resulting in endothelial shape change, pulmonary barrier disruption and edema. As such, TRPV4 blocker GSK2798745 was recently investigated in Phase I/IIa trials to reduce pulmonary edema caused by heart failure (HF). In the absence of a suitable TRPV4 target engagement biomarker, we hypothesized that an ex vivo assay could be utilized to predict pharmacological activity at the intended site of action (endothelial cells) of subjects. In this assay, the ability of GSK2798745 to block TRPV4 agonist GSK1016790-induced impendence reduction in human umbilical vein endothelial cells (HUVECs) in the presence of human whole blood was assessed. Blood from healthy volunteers drawn 1-12 h after single or repeated dose of GSK2798745 (5 mg) inhibited GSK1016790-induced impedance reduction by {greater than or equal to}85%. Similarly, blood samples from 16 HF subjects dosed with GSK2798745 (2.4 mg) inhibited GSK1016790-induced HUVEC impedance reduction by {greater than or equal to}58% 1-24 h after single dosing and {greater than or equal to}78% 1-24 h after 7 days of repeated dosing. No inhibition was detected using blood from placebo subjects. Using matched GSK2798745 plasma levels, a pharmacokinetic/pharmacodynamic (PK/PD) relationship was calculated as 2.9 nM IC50, consistent with the 6.5 nM IC50 of GSK2798745 obtained from a rat in vivo PK/PD model of pulmonary edema after correcting for rat-to-human differences. These results indicate circulating levels of GSK2798745 in the recently completed Phase I/IIa trials were sufficient to block TRPV4 in lung vascular endothelial cells to a large extent, supporting this dosing regimen for assessing efficacy in HF. Significance Statement In the absence of a suitable target engagement biomarker, we developed an ex vivo assay to predict the pharmacological activity of the TRPV4 blocker GSK2798745 in healthy volunteers and HF subjects from Phase I/IIa trials. The potency values from the ex vivo assay were consistent with those predicted from a rat in vivo PK/PD model of pulmonary edema, strongly suggest circulating levels of GSK2798745 were sufficient to robustly block TRPV4, supporting use of GSK2798745 for assessing efficacy in HF.

Allogeneic hematopoietic cell transplantation (HCT) remains the only curable option for adult patients with hematologic malignancies. According to guidelines published by the American Society for Transplantation and Cellular Therapy, allogeneic HCT should be offered to all intermediate‐ and high‐risk patients with acute leukemia. While matched‐related donor (MRD) grafts continue to be the preferred stem cell source for allogeneic HCT, studies comparing MRD grafts to matched‐unrelated donor (MUD) grafts showed comparable outcomes in patients with acute leukemia. Unfortunately, for those without a suitable matched‐related graft, the probability of finding a suitable matched‐unrelated donor varies significantly depending on racial and ethnic background. With allogeneic HCT procedures increasing year after year due to the increased availability of suitable donors, each of these alternative donor sources merits special clinical considerations, specifically with regards to infections. Infections remain a significant cause of morbidity and mortality after allogeneic transplant, especially in those receiving alternative donor graft. Due to the high‐risk nature associated with these donor grafts, it is important to understand the true risk of developing infectious complications. While there are a multitude of infections that have been described in patients post‐allogeneic HCT, this review seeks to focus on the incidence of cytomegalovirus (CMV) and invasive fungal infections (IFI) in adult patients receiving alternative donor source transplantation for hematologic malignancies.

Background Gepotidacin (GSK2140944) is a novel triazaacenaphthylene bacterial type II topoisomerase inhibitor in clinical development for the treatment of gonorrhea and uncomplicated UTI (acute cystitis). Gepotidacin selectively inhibits bacterial DNA gyrase and topoisomerase IV by a unique mechanism not utilized by any currently approved therapeutic agent and demonstrates in vitro activity against most target pathogens resistant to established antibacterials, including fluoroquinolones. This study tested the equivalency of minimal inhibitory concentrations (MICs) obtained by 2 reference susceptibility testing methods, agar dilution (AD) and broth microdilution (BMD), for gepotidacin against Gram-positive and Gram-negative organisms. Methods Susceptibility testing for both methods was performed on a total of 733 clinical isolates recovered largely in 2016 from over 120 medical centers worldwide. For N. gonorrhoeae, only the AD method is recommended by CLSI, therefore BMD was performed using Fastidious Broth for comparison purposes. Essential agreement (EA) based on evaluable results was calculated as the number of isolates with MICs within one 2-fold dilution of the reference method divided by the total number of results. Equivalency was defined using the 95% criteria from the FDA’s class II controls document. Results The EA observed for gepotidacin with these 2 methods was 85.8% overall and 98.3% when H. influenzae and N. gonorrhoeae isolates were excluded. Slightly higher gepotidacin MICs were observed when tested by BMD for each of these species/groups; this trend was especially prominent for E. coli and S. pyogenes. Gepotidacin tested against H. influenzae (73.1%) or N. gonorrhoeae (28.6%) species had much lower EAs. Conclusion Equivalency (EA >95%) was established between AD and BMD methods for determining gepotidacin susceptibility results against Staphylococcus spp., Streptococcus spp. and E. coli. However, for N. gonorrhoeae and H. influenzae, equivalency between the 2 methods was not established; therefore, future antimicrobial susceptibility testing for gepotidacin against these organisms should adhere to the methods for which quality control ranges and breakpoints are approved. Disclosures All authors: No reported disclosures.