Bristol-Myers Squibb (United Kingdom)

Immune checkpoint inhibitors have improved clinical outcomes associated with numerous cancers, but high-grade, immune-related adverse events can occur, particularly with combination immunotherapy. We report the cases of two patients with melanoma in whom fatal myocarditis developed after treatment with ipilimumab and nivolumab. In both patients, there was development of myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates. Selective clonal T-cell populations infiltrating the myocardium were identical to those present in tumors and skeletal muscle. Pharmacovigilance studies show that myocarditis occurred in 0.27% of patients treated with a combination of ipilimumab and nivolumab, which suggests that our patients were having a rare, potentially fatal, T-cell-driven drug reaction. (Funded by Vanderbilt-Ingram Cancer Center Ambassadors and others.) I mmune checkpoint inhibitors have transformed the treatment of several cancers by releasing restrained antitumor immune responses. 1 3] These toxic effects are more frequent and severe when ipilimumab and nivolumab are used in combination. Here, we report two cases of lethal myocarditis accompanied by myositis in patients treated with a combination of nivolumab and ipilimumab.

BACKGROUND: All-oral combination therapy is desirable for patients with chronic hepatitis C virus (HCV) infection. We evaluated daclatasvir (an HCV NS5A replication complex inhibitor) plus sofosbuvir (a nucleotide analogue HCV NS5B polymerase inhibitor) in patients infected with HCV genotype 1, 2, or 3. METHODS: In this open-label study, we initially randomly assigned 44 previously untreated patients with HCV genotype 1 infection and 44 patients infected with HCV genotype 2 or 3 to daclatasvir at a dose of 60 mg orally once daily plus sofosbuvir at a dose of 400 mg orally once daily, with or without ribavirin, for 24 weeks. The study was expanded to include 123 additional patients with genotype 1 infection who were randomly assigned to daclatasvir plus sofosbuvir, with or without ribavirin, for 12 weeks (82 previously untreated patients) or 24 weeks (41 patients who had previous virologic failure with telaprevir or boceprevir plus peginterferon alfa-ribavirin). The primary end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter) at week 12 after the end of therapy. RESULTS: Overall, 211 patients received treatment. Among patients with genotype 1 infection, 98% of 126 previously untreated patients and 98% of 41 patients who did not have a sustained virologic response with HCV protease inhibitors had a sustained virologic response at week 12 after the end of therapy. A total of 92% of 26 patients with genotype 2 infection and 89% of 18 patients with genotype 3 infection had a sustained virologic response at week 12. High rates of sustained virologic response at week 12 were observed among patients with HCV subtypes 1a and 1b (98% and 100%, respectively) and those with CC and non-CC IL28B genotypes (93% and 98%, respectively), as well as among patients who received ribavirin and those who did not (94% and 98%, respectively). The most common adverse events were fatigue, headache, and nausea. CONCLUSIONS: Once-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients infected with HCV genotype 1, 2, or 3, including patients with no response to prior therapy with telaprevir or boceprevir. (Funded by Bristol-Myers Squibb and Pharmasset (Gilead); A1444040 ClinicalTrials.gov number, NCT01359644.).

This paper reports interactions and possible incompatibilities in solid dispersions of hydrophobic drugs with hydrophilic carriers, with solubility parameters employed as a means of interpreting results. Systems containing ibuprofen (IB) and xylitol (XYL) in varying proportions and systems of IB with other sugars and a sugar polymer were produced using solvent evaporation and fusion methods. Additionally, bridging agents were employed with IB/XYL systems to facilitate the production of a solid dispersion. Results show that IB formed no interactions with any of the sugar carriers but interacted with all the bridging agents studied. The bridging agents were immiscible with XYL in the liquid state. Results of other reported drug/carrier systems and those from the systems studied in this paper were interpreted using Hildebrand solubility parameters. A trend between differences in drug/carrier solubility parameters and immiscibility was identified with incompatibilities evidence when large solubility parameter differences exist between drug and carrier. It was concluded that Hildebrand parameters give an indication of possible incompatibilities between drugs and carriers in solid dispersions, but that the use of partial solubility parameters may provide a more accurate prediction of interactions in and between materials and could provide more accurate indications of potential incompatibilities.

BACKGROUND: In biomedical research, it is often desirable to seek consensus among individuals who have differing perspectives and experience. This is important when evidence is emerging, inconsistent, limited, or absent. Even when research evidence is abundant, clinical recommendations, policy decisions, and priority-setting may still require agreement from multiple, sometimes ideologically opposed parties. Despite their prominence and influence on key decisions, consensus methods are often poorly reported. Our aim was to develop the first reporting guideline dedicated to and applicable to all consensus methods used in biomedical research regardless of the objective of the consensus process, called ACCORD (ACcurate COnsensus Reporting Document). METHODS AND FINDINGS: We followed methodology recommended by the EQUATOR Network for the development of reporting guidelines: a systematic review was followed by a Delphi process and meetings to finalize the ACCORD checklist. The preliminary checklist was drawn from the systematic review of existing literature on the quality of reporting of consensus methods and suggestions from the Steering Committee. A Delphi panel (n = 72) was recruited with representation from 6 continents and a broad range of experience, including clinical, research, policy, and patient perspectives. The 3 rounds of the Delphi process were completed by 58, 54, and 51 panelists. The preliminary checklist of 56 items was refined to a final checklist of 35 items relating to the article title (n = 1), introduction (n = 3), methods (n = 21), results (n = 5), discussion (n = 2), and other information (n = 3). CONCLUSIONS: The ACCORD checklist is the first reporting guideline applicable to all consensus-based studies. It will support authors in writing accurate, detailed manuscripts, thereby improving the completeness and transparency of reporting and providing readers with clarity regarding the methods used to reach agreement. Furthermore, the checklist will make the rigor of the consensus methods used to guide the recommendations clear for readers. Reporting consensus studies with greater clarity and transparency may enhance trust in the recommendations made by consensus panels.

The synthesis and functionalization of amines are fundamentally important in a vast range of chemical contexts. We present an amine synthesis that repurposes two simple feedstock building blocks: olefins and nitro(hetero)arenes. Using readily available reactants in an operationally simple procedure, the protocol smoothly yields secondary amines in a formal olefin hydroamination. Because of the presumed radical nature of the process, hindered amines can easily be accessed in a highly chemoselective transformation. A screen of more than 100 substrate combinations showcases tolerance of numerous unprotected functional groups such as alcohols, amines, and even boronic acids. This process is orthogonal to other aryl amine syntheses, such as the Buchwald-Hartwig, Ullmann, and classical amine-carbonyl reductive aminations, as it tolerates aryl halides and carbonyl compounds.

Abstract Two named reactions of fundamental importance and paramount utility in organic synthesis have been reinvestigated, the Barton decarboxylation and Giese radical conjugate addition. N ‐hydroxyphthalimide (NHPI) based redox‐active esters were found to be convenient starting materials for simple, thermal, Ni‐catalyzed radical formation and subsequent trapping with either a hydrogen atom source (PhSiH 3 ) or an electron‐deficient olefin. These reactions feature operational simplicity, inexpensive reagents, and enhanced scope as evidenced by examples in the realm of peptide chemistry.

This paper proposes the development of a drug product Manufacturing Classification System (MCS) based on processing route. It summarizes conclusions from a dedicated APS conference and subsequent discussion within APS focus groups and the MCS working party. The MCS is intended as a tool for pharmaceutical scientists to rank the feasibility of different processing routes for the manufacture of oral solid dosage forms, based on selected properties of the API and the needs of the formulation. It has many applications in pharmaceutical development, in particular, it will provide a common understanding of risk by defining what the "right particles" are, enable the selection of the best process, and aid subsequent transfer to manufacturing. The ultimate aim is one of prediction of product developability and processability based upon previous experience. This paper is intended to stimulate contribution from a broad range of stakeholders to develop the MCS concept further and apply it to practice. In particular, opinions are sought on what API properties are important when selecting or modifying materials to enable an efficient and robust pharmaceutical manufacturing process. Feedback can be given by replying to our dedicated e-mail address (mcs@apsgb.org); completing the survey on our LinkedIn site; or by attending one of our planned conference roundtable sessions.

The culture of Chinese Hamster Ovary (CHO) cells for modern industrial applications, such as expression of recombinant proteins, requires media that support growth and production. Such media must support high viable cell densities while also stimulating the synthesis and extracellular transport of biologic products. Early media development efforts in this area yielded basic formulations to sustain growth, viability, and cellular function, albeit comprising animal sourced components, and complex constituents used in batch culture mode. Subsequent improvements included the development of serum-free and chemically defined (CD) media, the identification of critical nutrients, growth factors, and potentially inhibitory or toxic cellular metabolites, and the use of fed-batch and perfusion culture techniques to optimize nutrient delivery while minimizing accumulation of unwanted waste products. This review is comprised of sections covering milestones in the evolution of mammalian cell culture media, nutrient composition and formulation requirements, optimization strategies, consistency and scalability of powder and liquid media preparation for industrial applications, and key recent advances driving progress in CHO cell culture medium design and development. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:1407-1426, 2018.

OBJECTIVES: While plasma biomarkers have been proposed to aid in the clinical diagnosis of Alzheimer disease (AD), few biomarkers have been validated in independent patient cohorts. Here we aim to determine plasma biomarkers associated with AD in 2 independent cohorts and validate the findings in the multicenter Alzheimer's Disease Neuroimaging Initiative (ADNI). METHODS: Using a targeted proteomic approach, we measured levels of 190 plasma proteins and peptides in 600 participants from 2 independent centers (University of Pennsylvania, Philadelphia; Washington University, St. Louis, MO), and identified 17 analytes associated with the diagnosis of very mild dementia/mild cognitive impairment (MCI) or AD. Four analytes (apoE, B-type natriuretic peptide, C-reactive protein, pancreatic polypeptide) were also found to be altered in clinical MCI/AD in the ADNI cohort (n = 566). Regression analysis showed CSF Aβ42 levels and t-tau/Aβ42 ratios to correlate with the number of APOE4 alleles and plasma levels of B-type natriuretic peptide and pancreatic polypeptide. CONCLUSION: Four plasma analytes were consistently associated with the diagnosis of very mild dementia/MCI/AD in 3 independent clinical cohorts. These plasma biomarkers may predict underlying AD through their association with CSF AD biomarkers, and the association between plasma and CSF amyloid biomarkers needs to be confirmed in a prospective study.

BACKGROUND: Therapeutic decisions regarding pharmacological therapy should be based on safety and tolerability as well as efficacy data. Clinical trials designed to assess efficacy are often insufficiently powered to generate reliable safety data. METHODS AND RESULTS: The West of Scotland Coronary Prevention Study (WOSCOPS), the Cholesterol and Recurrent Events (CARE), and Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) studies collectively accumulated >112 000 person-years of exposure in double-blind randomized trials comparing placebo and pravastatin (40 mg once daily). During 5 years of exposure, the incidence of fatal and nonfatal cancers was similar between pravastatin and placebo groups. No differences in noncardiovascular serious adverse events were detected. With >243 000 blood sample analyses, the percentage of patients with any abnormal liver function test after baseline sampling was similar (>3x the upper limit of normal for alanine aminotransferase: 128 [1.4%] versus 131 [1.4%] patients for pravastatin versus placebo, respectively). Study medication was withdrawn in 3 pravastatin and 7 placebo patients due to creatine phosphokinase elevations; no cases of mild or severe myopathy were reported. A Cox regression model considering treatment group, age, diabetes, smoking, whether primary or secondary prevention study, and cardiovascular serious adverse events indicates that the likelihood of discontinuing pravastatin was less than placebo. CONCLUSIONS: This prospective analysis indicates that during prolonged exposure, 40 mg of pravastatin is well tolerated, with no excess of noncardiovascular serious adverse events, including liver function abnormalities and laboratory and clinical evidence for myositis. These extensive safety and tolerability data provide important information for therapeutic decisions regarding this pharmacological agent.

OBJECTIVE: To provide an update on glycaemic control in European patients with type 2 diabetes based on data from the nine-country, cross-sectional PANORAMA study (NCT00916513). DESIGN: Post-hoc analysis to report the number of patients achieving/not achieving glycaemic goal (HbA(1c) <7%). PATIENTS: Patients were randomly or consecutively selected from physician practices in nine countries. Eligible patients were aged ≥40 years, diagnosed with type 2 diabetes >1 year prior to study entry, and had an available medical record of >1 year. MEASUREMENTS: All data were collected at a single visit, including HbA1c measurement using a common device (A1CNow). Bivariate and multivariate analyses were used to investigate factors associated with not reaching glycaemic goal. RESULTS: Of 5817 patients enrolled (aged 65·9 ± 10·4 years, 53·7% male), 37·4% had an HbA(1c) ≥7%; (range 25·9% in The Netherlands to 52·0% in Turkey). In adjusted multivariate analyses, higher individual glycaemic target, younger age, poor physician-reported patient adherence to lifestyle/medication, longer diabetes duration, increasing treatment regimen complexity and physician-reported patient's unwillingness to intensify treatment were associated with not achieving goal. However, bivariate analyses also found gender, socioeconomic factors, body mass index, rate of complications and hypoglycaemia to be associated with not achieving goal. CONCLUSIONS: In PANORAMA, 37·4% of patients enrolled were not at glycaemic goal. Factors relating to patient characteristics, physician selection of individualized HbA1c target and diabetes itself (longer duration, more complex treatment) were strongly associated with not achieving goal. Further studies are warranted to explore these associations and evaluate strategies for improving glycaemic control.

OBJECTIVE: To compare the efficacy and safety of subcutaneous (SC) and intravenous (IV) abatacept. METHODS: In this phase IIIb double-blind, double-dummy, 6-month study, patients with rheumatoid arthritis (RA) and inadequate responses to methotrexate were randomized to receive 125 mg SC abatacept on days 1 and 8 and weekly thereafter (plus an IV loading dose [∼10 mg/kg] on day 1) or IV abatacept (∼10 mg/kg) on days 1, 15, and 29 and every 4 weeks thereafter. The primary end point for determining the noninferiority of SC abatacept to IV abatacept was the proportion of patients in each group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at month 6. Other efficacy end points, immunogenicity, and safety were also assessed. RESULTS: Of 1,457 patients, 693 of 736 (94.2%) treated with SC abatacept and 676 of 721 (93.8%) treated with IV abatacept completed 6 months. At month 6, 76.0% (95% confidence interval 72.9, 79.2) of SC abatacept-treated patients versus 75.8% (95% confidence interval 72.6, 79.0) of IV abatacept-treated patients achieved an ACR20 response (estimated difference between groups 0.3% [95% confidence interval -4.2, 4.8]), confirming noninferiority of SC abatacept to IV abatacept. Onset and magnitude of ACR responses and disease activity and physical function improvements were comparable between the SC and IV abatacept-treated groups. The proportions of adverse events (AEs) and serious AEs over 6 months were 67.0% and 4.2%, respectively, in the SC abatacept-treated group and 65.2% and 4.9%, respectively, in the IV abatacept-treated group, with comparable frequencies of serious infections, malignancies, and autoimmune events between groups. SC injection site reactions (mostly mild) occurred in 19 SC abatacept (IV placebo)-treated patients (2.6%) and 18 IV abatacept (SC placebo)-treated patients (2.5%). Abatacept-induced antibodies occurred in 1.1% of SC abatacept-treated patients and 2.3% of IV abatacept-treated patients. CONCLUSION: SC abatacept provides efficacy and safety comparable with that of IV abatacept, with low immunogenicity and high retention rates, consistent with the established IV abatacept profile. Rates of injection site reactions were low. SC abatacept will provide additional treatment options, such as an alternative route of administration, for patients with RA.

After decades of warfarin being the only oral anticoagulant (OAC) widely available for stroke prevention in atrial fibrillation, four direct OACs (apixaban, dabigatran, edoxaban and rivaroxaban) were approved after demonstrating noninferior efficacy and safety versus warfarin in randomized controlled trials. Comparative effectiveness research of OACs based on real-world data provides complementary information to randomized controlled trials. Propensity score matching and inverse probability of treatment weighting are increasingly popular methods used to address confounding by indication potentially arising in comparative effectiveness research due to a lack of randomization in treatment assignment. This review describes the fundamentals of propensity score matching and inverse probability of treatment weighting, appraises differences between them and presents applied examples to elevate understanding of these methods within the atrial fibrillation field.

UNLABELLED: The antiviral activity, resistance profile, pharmacokinetics (PK), safety, and tolerability of BMS-790052, a nonstructural protein 5A (NS5A) replication complex inhibitor, were evaluated in a double-blind, placebo-controlled, sequential panel, multiple ascending dose study. Thirty patients with chronic hepatitis C virus (HCV) genotype 1 infection were randomized to receive a 14-day course of BMS-790052 (1, 10, 30, 60, or 100 mg once daily or 30 mg twice daily) or placebo in a ratio of 4:1. The mean maximum decline from baseline in HCV RNA ranged from 2.8 to 4.1 log(10) IU/mL; the placebo group showed no evidence of antiviral activity. Most patients experienced viral rebound on or before day 7 of treatment with BMS-790052 monotherapy; viral rebound was associated with viral variants that had been previously implicated in resistance development in the in vitro replicon system. The PK profile was supportive of once-daily dosing with median peak plasma concentrations at 1-2 hours postdose and mean terminal half-life of 12-15 hours. Steady state was achieved following 3-4 days of daily dosing. BMS-790052 was well tolerated in all dose groups, with adverse events occurring with a similar frequency in BMS-790052- and placebo-treated groups. There were no clinically relevant changes in vital signs, laboratory, or electrocardiogram parameters. CONCLUSION: BMS-7590052 is the first NS5A replication complex inhibitor with multiple dose proof-of-concept in clinic. At doses of 1-100 mg daily, BMS-790052 was well tolerated, had a PK profile supportive of once-daily dosing, and produced a rapid and substantial decrease in HCV-RNA levels in patients chronically infected with HCV genotype 1.

P B Woods, M L Robinson; An investigation of the comparative liposolubilities of β-adrenoceptor blocking agents, Journal of Pharmacy and Pharmacology, Volu

OBJECTIVE: Early diagnosis and treatment initiation significantly influence long-term disability outcome in multiple sclerosis (MS). We aimed at identifying prodromal symptoms of MS in primary care settings. METHODS: This was a nested case-control study comparing the occurrence of various symptoms in MS patients versus controls at 0 to 2, 2 to 5, and 5 to 10 years before index date (first MS record). A total of 10,204 incident MS cases were identified within the United Kingdom Clinical Practice Research Datalink between January 1, 1987 and February 28, 2016 (median age = 47 years, interquartile range [IQR] = 39-57, females = 7,308 [71.6%]). Patients were matched to 39,448 controls with no MS record by sex, year of birth, general practitioner, and year of registration (age = 47 years, IQR = 39-56, females = 28,248 [71.6%]). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using conditional logistic regression. RESULTS: MS patients had significantly higher risk of presenting up to 10 years prior to index date with gastric, intestinal, urinary, and anorectal disturbances, anxiety, depression, insomnia, fatigue, headache, and various types of pain. MS risk progressively increased with each additional symptom presented (0-2 years: OR = 1.51, 95% CI = 1.47-1.55, p < 0.001; 2-5 years: OR = 1.29, 95% CI = 1.25-1.33, p < 0.001; 5-10 years: OR = 1.20, 95% CI = 1.15-1.26, p < 0.001). Sensitivity analyses in patients with age at index < 40 years and no neurological disturbances prior to symptoms of interest showed consistent results. INTERPRETATION: Various clinical disturbances precede MS diagnosis by several years, supporting a prodromal phase to the disease and improving our clinical knowledge of early MS. Integrating these symptoms in the diagnostic procedure may help earlier disease identification. Ann Neurol 2018.

Real-time monitoring of bioprocesses by the integration of analytics at critical unit operations is one of the paramount necessities for quality by design manufacturing and real-time release (RTR) of biopharmaceuticals. A well-defined process analytical technology (PAT) roadmap enables the monitoring of critical process parameters and quality attributes at appropriate unit operations to develop an analytical paradigm that is capable of providing real-time data. We believe a comprehensive PAT roadmap should entail not only integration of analytical tools into the bioprocess but also should address automated-data piping, analysis, aggregation, visualization, and smart utility of data for advanced-data analytics such as machine and deep learning for holistic process understanding. In this review, we discuss a broad spectrum of PAT technologies spanning from vibrational spectroscopy, multivariate data analysis, multiattribute chromatography, mass spectrometry, sensors, and automated-sampling technologies. We also provide insights, based on our experience in clinical and commercial manufacturing, into data automation, data visualization, and smart utility of data for advanced-analytics in PAT. This review is catered for a broad audience, including those new to the field to those well versed in applying these technologies. The article is also intended to give some insight into the strategies we have undertaken to implement PAT tools in biologics process development with the vision of realizing RTR testing in biomanufacturing and to meet regulatory expectations.

AIMS: To assess initial pharmacotherapy of Type 2 diabetes with the sodium-glucose cotransporter-2 inhibitor dapagliflozin. METHODS: This double-blind, placebo-controlled trial, randomly allocated people with Type 2 diabetes aged 18-77 years and inadequate glycaemic control on diet and exercise [HbA1c 53-86 mmol/mol (7.0-10.0%)] to receive placebo (n = 75) or dapagliflozin monotherapy 2.5 mg (n = 65), 5 mg (n = 64) or 10 mg (n = 70) once daily in the morning. After 24 weeks, low-dose double-blind metformin 500 mg/day was added to the placebo group regimen (placebo+low-dose metformin group). Changes in HbA1c level, fasting plasma glucose and body weight, as well as adverse events, were assessed over 102 weeks. RESULTS: Of the 274 participants randomized, 167 completed the study (60.9%). At 102 weeks, significant differences vs placebo+low-dose metformin with dapagliflozin 5 and 10 mg were observed for HbA1c (-5.8 mmol/mol [-0.53%], P = 0.018; and -4.8 mmol/mol [-0.44%], P = 0.048), respectively); and for FPG (-0.69 mmol/L, P = 0.044; and -1.12 mmol/l, P = 0.001, respectively). For body weight, the difference between the dapagliflozin 10-mg group and the placebo+low-dose metformin group was significant (-2.60 kg; P = 0.016). Hypoglycaemic events were uncommon, with rates of 5.3% for placebo+low-dose metformin group and 0-4.6% for the dapagliflozin groups. Genital infections and urinary tract infections were more common in the dapagliflozin groups than in the placebo+low-dose metformin group. CONCLUSIONS: Dapagliflozin as monotherapy in treatment-naïve people with early Type 2 diabetes improved glycaemic control and reduced weight without increasing hypoglycaemia over 102 weeks. Dapagliflozin may provide an alternative initial pharmacotherapy in such people.

The development of a new decarboxylative cross-coupling method that affords terminal and substituted alkynes from various carboxylic acids is described using both nickel- and iron-based catalysts. The use of N-hydroxytetrachlorophthalimide (TCNHPI) esters is crucial to the success of the transformation, and the reaction is amenable to in situ carboxylic acid activation. Additionally, an inexpensive, commercially available alkyne source is employed in this formal homologation process that serves as a surrogate for other well-established alkyne syntheses. The reaction is operationally simple and broad in scope while providing succinct and scalable avenues to previously reported synthetic intermediates.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained heart arrhythmia. However, as many cases are asymptomatic, a large proportion of patients remain undiagnosed until serious complications arise. Efficient, cost-effective detection of the undiagnosed may be supported by risk-prediction models relating patient factors to AF risk. However, there exists a need for an implementable risk model that is contemporaneous and informed by routinely collected patient data, reflecting the real-world pathology of AF. METHODS: This study sought to develop and evaluate novel and conventional statistical and machine learning models for risk-predication of AF. This was a retrospective, cohort study of adults (aged ≥30 years) without a history of AF, listed on the Clinical Practice Research Datalink, from January 2006 to December 2016. Models evaluated included published risk models (Framingham, ARIC, CHARGE-AF), machine learning models, which evaluated baseline and time-updated information (neural network, LASSO, random forests, support vector machines), and Cox regression. RESULTS: Analysis of 2,994,837 individuals (3.2% AF) identified time-varying neural networks as the optimal model achieving an AUROC of 0.827 vs. 0.725, with number needed to screen of 9 vs. 13 patients at 75% sensitivity, when compared with the best existing model CHARGE-AF. The optimal model confirmed known baseline risk factors (age, previous cardiovascular disease, antihypertensive medication usage) and identified additional time-varying predictors (proximity of cardiovascular events, body mass index (both levels and changes), pulse pressure, and the frequency of blood pressure measurements). CONCLUSION: The optimal time-varying machine learning model exhibited greater predictive performance than existing AF risk models and reflected known and new patient risk factors for AF.