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Background and Objectives: Ubrogepant is a calcitonin gene-related peptide receptor antagonist approved for the acute treatment of migraine. The PRODROME trial previously demonstrated that ubrogepant treatment during prodrome prevents the onset of moderate or severe headache. In this analysis of the PRODROME trial, the benefits of ubrogepant treatment during the prodrome on patient-reported outcomes (PROs) are evaluated., Methods: PRODROME was a multicenter, randomized, double-blind, placebo-controlled, crossover trial that enrolled adults who experienced 2-8 migraine attacks per month with moderate-severe headache pain. Eligible participants treated 2 qualifying prodrome events, defined as a migraine attack with prodromal symptoms when the participant was confident a headache would follow within 1-6 hours. Participants were randomized to treatment sequence A (placebo then ubrogepant 100 mg) or sequence B (ubrogepant 100 mg then placebo). This analysis evaluated the ability to function normally over 24 hours (secondary end point) and at specific time points after dose (additional end point). Other PRO end points included activity limitation over 24 hours and satisfaction with study medication at 8 and 24 hours., Results: Of 518 randomized participants, 477 comprised the modified intent-to-treat population. After treatment of qualifying prodrome events, a significantly greater ability to function normally over 24 hours was observed for participants after treatment with ubrogepant 100 mg compared with placebo (odds ratio [OR] 1.66, 95% CI 1.40-1.96; p < 0.0001). As early as 2 hours after dose, a greater proportion of ubrogepant-treated participants reported "no disability, able to function normally" compared with placebo (OR 1.76, 95% CI 1.32-2.35; nominal p = 0.0001). Ubrogepant administered during the prodrome was also associated with a greater reduction in activity limitations over 24 hours after dose (OR 2.07, 95% CI 1.61-2.67; nominal p < 0.0001). At 8 and 24 hours after dose, rates of being "satisfied" or "extremely satisfied" were greater for ubrogepant than for placebo (8 hours: OR 2.37, 95% CI 1.78-3.15; nominal p < 0.0001; 24 hours: OR 2.32, 95% CI 1.78-3.02; nominal p < 0.0001)., Discussion: Ubrogepant 100 mg administered during the prodrome was associated with significantly greater ability to function normally, greater reduction in activity limitations over 24 hours, and greater satisfaction with study medication, compared with placebo., Trial Registration Information: ClinicalTrials.gov NCT04492020. Submitted: July 27, 2020; first patient enrolled: August 21, 2020. clinicaltrials.gov/ct2/show/NCT04492020., Classification of Evidence: This study provides Class II evidence that taking ubrogepant 100 mg during a migraine prodrome allows more patients to function normally over the next 24 hours.

Determining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD., (© 2024. The Author(s).)

Background: The SkinMedica Acne Treatment Platform (SM Regimen) was formulated to treat acne without overdrying the skin. We evaluated efficacy and tolerability of the SM Regimen (including a novel 1% salicylic acid Acne Clarifying Cleanser and 2% salicylic acid Acne Treatment Lotion) versus a prescription formulation (Rx Regimen; including adapalene 0.1%/benzoyl peroxide 2.5%) in a diverse population of adults with mild to moderate facial acne., Methods: This single-center, double-blind, randomized study enrolled adults (18-45 years) with Fitzpatrick skin types (FST) I-VI. SM Regimen or Rx Regimen was applied topically to the entire face for 12 weeks. Assessments were conducted at 24 and 48 h and 4, 8, and 12 weeks., Results: Subjects (SM Regimen, n = 31; Rx Regimen, n = 23) were primarily female (90.7%) with mean age of 28.6 years; 53.8% had FST IV-VI. Efficacy was comparable between regimens. The SM regimen resulted in significant improvements versus baseline in mean Investigator's Global Assessment of acne severity from 48 h through week 12 (p ≤ 0.001), as well as significant and sustained improvements from baseline in total acne lesion count, global postinflammatory hyperpigmentation/postinflammatory erythema, and oiliness. The SM Regimen was well tolerated at all time points, with mean scores below mild for all parameters; the Rx Regimen caused significantly more tightness/dry feeling at week 4 versus SM Regimen (p = 0.008). Subjects (> 96%) reported high satisfaction with the SM Regimen at all time points., Conclusions: The SM Regimen reduced acne severity and skin oiliness, evening out skin tone without overdrying or irritating the skin., (© 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Background and Objectives: Up to 30% of psoriasis (PsO) is clinically associated with psoriatic arthritis (PsA). A large proportion of new onset of PsA is diagnosed at a later stage, despite the necessity of early effective treatment to prevent structural damage. This study aimed to identify the routine screening practices used for PsA in patients with PsO., Patients and Methods: This non-interventional, prospective, epidemiological, cross-sectional study conducted in Germany focuses on screening activity and treatment selection of dermatological practices in suspected PsA. Descriptive statistics and patient characteristics were analyzed for different center types., Results: One hundred ninety-five patients from 34 office-based physicians, five non-university hospitals, and nine university hospitals were included. Questionnaires or imaging techniques were not routinely used (< 45%). Especially, ultrasounds (≤ 5%) and MRIs (< 6.3%) were rarely performed. Between 30% and 75% of suspected PsA could be confirmed. Referral to rheumatologists and/or appropriate therapy initiation were the most frequent consequences., Conclusions: Results of this study reflect the status of PsA screening activity by dermatologists. Imaging techniques, particularly ultrasound or MRIs to detect early forms of PsA, were inadequately used, which may have contributed to continued underdiagnoses. Collaboration between dermatologists and rheumatologists should be reviewed with a view to improving effective PsA screening., (© 2024 The Author(s). Journal der Deutschen Dermatologischen Gesellschaft published by Wiley‐VCH GmbH on behalf of Deutsche Dermatologische Gesellschaft.)

Adverse drug events (ADEs) are one of the major causes of hospital admissions and are associated with increased morbidity and mortality. Post-marketing ADE identification is one of the most important phases of drug safety surveillance. Traditionally, data sources for post-marketing surveillance mainly come from spontaneous reporting system such as the Food and Drug Administration Adverse Event Reporting System (FAERS). Social media data such as posts on X (formerly Twitter) contain rich patient and medication information and could potentially accelerate drug surveillance research. However, ADE information in social media data is usually locked in the text, making it difficult to be employed by traditional statistical approaches. In recent years, large language models (LLMs) have shown promise in many natural language processing tasks. In this study, we developed several LLMs to perform ADE classification on X data. We fine-tuned various LLMs including BERT-base, Bio&#95;ClinicalBERT, RoBERTa, and RoBERTa-large. We also experimented ChatGPT few-shot prompting and ChatGPT fine-tuned on the whole training data. We then evaluated the model performance based on sensitivity, specificity, negative predictive value, positive predictive value, accuracy, F1-measure, and area under the ROC curve. Our results showed that RoBERTa-large achieved the best F1-measure (0.8) among all models followed by ChatGPT fine-tuned model with F1-measure of 0.75. Our feature importance analysis based on 1200 random samples and RoBERTa-Large showed the most important features are as follows: "withdrawals"/"withdrawal", "dry", "dealing", "mouth", and "paralysis". The good model performance and clinically relevant features show the potential of LLMs in augmenting ADE detection for post-marketing drug safety surveillance.

Background: HA/CaHa (HArmonyCa, Allergan Aesthetics, an AbbVie Company) is a hybrid injectable filler developed for aesthetic purposes that contains calcium hydroxyapatite microspheres suspended in a hyaluronic acid gel. This review describes preclinical and clinical data, recommendations for use based on the primary author's clinical experience, and case studies that illustrate implementation of product use recommendations and patient outcomes., Methods: Preclinical data on the lift capacity and tissue integration of the HA/CaHa hybrid injectable and clinical data on its safety, efficacy, and real-world use were extracted from poster presentations, published literature, manufacturer instructions for use, and proprietary data files. Case studies were presented based on clinical experience., Results: The HA component of HA/CaHa provides an immediate and noticeable filling and lifting effect, whereas CaHa microspheres result in neocollagenesis. In preclinical studies, HA/CaHa demonstrated higher lift capacity ( P < 0.05) and faster tissue integration than a CaHa filler and led to collagen I gene and protein expression. Clinical studies showed clinical safety and effectiveness with high patient satisfaction. The most common adverse event was injection-site response. Clinician recommendations for achieving desired aesthetic results while minimizing or preventing adverse events are reviewed, including patient selection and assessment, treatment approaches based on face shape, injection technique, and postprocedure care., Conclusion: The novel hybrid injectable consisting of HA with incorporated CaHa microspheres in a single marketed product may help achieve aesthetic goals by immediately restoring volume and potentially improving skin architecture and soft-tissue quality over time., Competing Interests: Dr. Braz is a speaker, advisor and investigator for Allergan Aesthetics, an AbbVie Company. Drs. Cazerta de Paula Eduardo, Pierce, Grond, Kutikov, and Nakab are full-time employees of AbbVie. Allergan Aesthetics, an AbbVie Company, funded this work and participated in the design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing support was provided to the authors by Adrienne Drinkwater, PhD, and Regina Kelly, MA, of Peloton Advantage LLC, an OPEN Health Company, Parsippany, NJ, and funded by Allergan Aesthetics, an AbbVie company., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Background: Drug-induced liver injury (DILI) is a major concern for oncology drugs in clinical practice and under development. Monitoring cancer patients for hepatotoxicity is challenging as these patients may have abnormal liver tests pre-treatment or on-study for many reasons including liver injury due to past oncology treatments, hepatic metastases, medical co-morbidities such as heart failure, and concomitant medications. At present, there are no regulatory guidelines or position papers that systematically address best practices pertaining to DILI detection, assessment and management in oncology patients., Aims: The goals of this review are (1) to examine and interpret the available evidence and (2) to make recommendations for detection, monitoring, adjudication, and management of suspected hepatocellular DILI during oncology clinical trials., Methods: This manuscript was developed by the IQ Consortium (International Consortium for Innovation and Quality in pharmaceutical development) DILI Initiative that consists of members from 17 pharmaceutical companies, in collaboration with academic and regulatory DILI experts. The manuscript is based on extensive literature review, expert interpretation of the literature, and several rounds of consensus discussions., Results: This review highlights recommendations for patient eligibility for clinical trials with or without primary/metastatic liver involvement, as well as changes in liver tests that should trigger increased monitoring and/or discontinuation of study drug. Guidance regarding causality assessment for suspected DILI events, rechallenge and dose-modification is provided., Conclusions: This review brings together evidence-based recommendations and expert opinion to provide the first dedicated consensus for best practices in detection, assessment, and management of DILI in oncology clinical trials., (© 2024 John Wiley & Sons Ltd.)

Background and Aim: Suboptimal disease control (SDC) and its contributing factors in IBD according to STRIDE-II criteria is unclear. IBD-PODCAST was a non-interventional, international, multicenter real-world study to assess this., Methods: Data from the Italian IBD cohort (N=220) are presented here. Participants aged ≥19 with confirmed IBD diagnosis of ≥1 year were consecutively enrolled. A retrospective chart review and cross-sectional assessment by physicians and patients within the past 12 months were performed. SDC or optimal disease control was assessed using adapted STRIDE-II criteria., Results: At the index date, 53.4 % of 116 CD patients and 49.0 % of 104 UC patients had SDC, mainly attributed to a Short Inflammatory Bowel Disease Questionnaire score <50, failure to achieve endoscopic remission, and the presence of active extra-intestinal manifestations in both diseases. Disease monitoring with imaging and/or endoscopy during the previous year was conducted in ∼50 % of patients, with endoscopy performed in ∼40 %. Potential therapeutic adjustments were reported for half of the patients., Conclusions: This study highlights SDC in a significant portion of IBD Italian patients. These results emphasize the need for more proactive management strategies in both CD and UC patients., Competing Interests: Competing interests, (Copyright © 2024. Published by Elsevier Ltd.)

This article highlights the profound impact of Professor Lynne S. Taylor, Retter Distinguished Professor of Pharmacy at Purdue University, on her mentees in terms of scientific and professional experience. The former students summarize some of her important contributions, including her emphasis on critical thinking, collaboration, and work-life balance, which have shaped her students into dedicated scientists advancing the pharmaceutical sciences. This acknowledgment recognizes her valuable impact on both her students and the broader scientific community., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Seizure-related homolog protein 6 (SEZ6) is a novel target expressed in small cell lung cancer (SCLC). ABBV-011, a SEZ6-targeted antibody conjugated to calicheamicin, was evaluated in a phase I study (NCT03639194) in patients with relapsed/refractory SCLC. We report initial outcomes of ABBV-011 monotherapy., Patients and Methods: ABBV-011 was administered intravenously once every 3 weeks (Q3W) during dose escalation (0.3-2 mg/kg) and expansion. Patients with SEZ6-positive tumors (≥25% of tumor cells with ≥1+ staining intensity by immunohistochemistry) were preselected for expansion. Safety, tolerability, antitumor activity, and pharmacokinetics were evaluated., Results: As of August 2022, 99 patients received ABBV-011 monotherapy (dose escalation, n=36; Japanese dose evaluation, n=3; dose expansion, n=60 [1 mg/kg, n=40]); median age was 63 years (range, 41-79). Thirty-two percent, 41%, and 26% of patients received 1, 2, and ≥3 prior therapies, respectively. The maximum tolerated dose was not reached through 2.0 mg/kg. Most common treatment-emergent adverse events (TEAEs) were fatigue (50%), nausea (42%), and thrombocytopenia (41%). Most common hepatic TEAEs were increased aspartate aminotransferase (22%), increased g-glutamyltransferase (21%), and hyperbilirubinemia (17%); 2 patients experienced veno-occlusive liver disease. Objective response rate (ORR) was 19% (19/98). In the 1-mg/kg dose-expansion cohort (n=40), ORR was 25%; median response duration was 4.2 months (95% CI, 2.6-6.7) and median progression-free survival was 3.5 months (95% CI, 1.5-4.2)., Conclusions: ABBV-011 1.0 mg/kg Q3W monotherapy was well tolerated and demonstrated encouraging antitumor activity in heavily pretreated patients with relapsed/refractory SCLC. SEZ6 is a promising novel SCLC target and warrants further investigation.

Introduction: Combination use of atogepant and onabotulinumtoxinA has the potential to be more effective than either alone for the preventive treatment of chronic migraine (CM) due to their complementary mechanisms of action. This analysis collected real-world data to evaluate the safety, tolerability, and effectiveness of adding atogepant to onabotulinumtoxinA as a combination preventive treatment for CM., Methods: This retrospective, longitudinal, multicenter chart review included adults with CM who received ≥ 2 consecutive cycles of onabotulinumtoxinA before ≥ 1 month of onabotulinumtoxinA and atogepant combination treatment. Charts at atogepant prescription (index date) and two subsequent onabotulinumtoxinA treatment visits (~ 3 and ~ 6 months post-index) were reviewed for change from baseline in monthly headache days (MHDs), ≥ 50% reduction in MHDs, discontinuation rates, and adverse events (AEs)., Results: Of the 55 charts that met safety analysis criteria, 31 had data on headache days at index and first post-index visit and were eligible for effectiveness analysis (mean age 46.7 years, 94.5% female). For those with data available prior to onabotulinumtoxinA treatment (n = 25), the mean MHD was 24.0 days, reduced by 8.15 days after onabotulinumtoxinA treatment. After atogepant was added, MHD was incrementally reduced by 4.53 days and 8.75 days from index date to the first (N = 31) and second (N = 23) post-index onabotulinumtoxinA treatment visit, respectively. A ≥ 50% reduction in MHDs was achieved by 45.2% of patients ~ 3 months post-index. Atogepant and onabotulinumtoxinA were discontinued by 16.1% and 6.5% of patients, respectively. In the safety population, 32.7% of patients experienced ≥ 1 AE. No serious AEs were reported., Conclusions: This real-world study of patients with CM demonstrated that adding atogepant to onabotulinumtoxinA as a combination preventive treatment for CM was effective by providing an additional reduction in MHDs over ~ 3 and ~ 6 months of combination treatment. Safety results were consistent with the known safety profiles of onabotulinumtoxinA and atogepant, with no new safety signals identified., (© 2024. The Author(s).)

Importance: The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown., Objective: To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis., Design, Setting, and Participants: Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab., Interventions: For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks., Main Outcomes and Measures: The primary outcome was clinical remission (stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial., Results: Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P < .001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P < .001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P = .002). No new safety risks were detected in the treatment groups., Conclusion and Relevance: Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up., Trial Registration: ClinicalTrials.gov Identifiers: NCT03398148 and NCT03398135.

Optimization of ICH safety guideline studies for inclusion into regulatory submissions is critical for resource conservation, animal use reduction, and efficient drug development. The ICH S7A guidance for Safety Pharmacology (SP) studies adopted in 2001 identified the core battery of studies to evaluate the acute safety of putative pharmaceutical molecules prior to First in Human (FIH) trials. To assess the utility of respiratory studies in predicting clinical AE's, seven pharmaceutical companies pooled preclinical and clinical respiratory findings. A large database of novel molecules included all relevant data from standard S7A respiratory (n = 459) and FIH studies (n = 309). The data were analyzed with respect to the progression of these molecules, clinical adverse event reporting of these same molecules, and achieved exposures. These S7A respiratory assay findings had no impact on compound progression, and only 12 of 309 drug candidates were 'positive' preclinically and reported a respiratory-related AE in clinical trials (i.e. cough, dyspnea, etc.), an overall incidence rate of 3.9%. Contingency tables/statistics support a lack of concordance of these preclinical assays. Overall, our extensive analysis clearly indicated that the preclinical respiratory assay fails to provide any prognostic value for detecting clinically relevant respiratory adverse events., Competing Interests: Declaration of Competing Interest Authors voluntarily interrogated their respective internal databases to populate the common spreadsheet. All efforts were internally funded; no external funding was utilized. There are no conflicts of interest to disclose by any of the authors of the manuscript. other than their employment in commercial biopharmaceutical companies. No information is presented in this paper that advocates for or promotes commercial products from any of our organizations., (Copyright © 2024. Published by Elsevier Inc.)

TAM receptor tyrosine kinases have emerged as promising therapeutic targets for cancer treatment due to their roles in both tumor intrinsic survival mechanisms and suppression of antitumor immunity within the tumor microenvironment. Inhibiting MerTK and Axl selectively is believed to hinder cancer cell survival, reverse the protumor myeloid phenotype, and suppress efferocytosis, thereby eliciting an antitumor immune response. In this study, we present the discovery of A-910 , a highly potent and selective dual MerTK/Axl inhibitor, achieved through a structure-based medicinal chemistry campaign. The lead compound exhibits favorable oral bioavailability, exceptional kinome selectivity, and significantly improved in vivo target engagement. These findings support the use of A-910 as an orally bioavailable in vivo tool compound for investigating the immunotherapy potential of dual MerTK/Axl inhibition.

A Suzuki-Miyaura cross-coupling reaction was developed on unprotected ortho -bromoanilines. This operationally simple reaction was developed for the diversification of glucocorticoid receptor modulators (GRMs), showed compatibility to various boronic esters featuring unique functionalities, and was demonstrated on a gram scale., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

1. Isolated perfused rat liver (IPRL) experiments have been used to answer clearance-related questions, including evaluating the impact of pathological and physiological processes on hepatic clearance (CL H ). However, to date, IPRL data has not been evaluated for in vivo CL H prediction accuracy.2. In addition to a detailed overview of available IPRL literature, we present an in-depth analysis of the performance of IPRL in CL H prediction.3. While the entire dataset poorly predicted CL H (GAFE = 3.2; 64% within 3-fold), IPRL conducted under optimal experimental conditions, such as in the presence of plasma proteins and with a perfusion rate within 2-fold of physiological liver blood flow and corrected for unbound fraction in the presence of red blood cells, can accurately predict rat CL H (GAFE = 2.0; 78% within 3-fold). Careful consideration of experimental conditions is needed to allow proper data analysis.4. Further, isolated perfused liver experiments in other species, including human livers, may allow us to address the current in vitro - in vivo disconnects of hepatic metabolic clearance and improve our methodology for CL H predictions.

Hepatic clearance ( CL H ) prediction is a critical parameter to estimate human dose. However, CL H underpredictions are common, especially for slowly metabolized drugs, and may be attributable to drug properties that pose challenges for conventional in vitro absorption, distribution, metabolism, and elimination (ADME) assays, resulting in nonvalid data, which prevents in vitro to in vivo extrapolation and CL H predictions. Other processes, including hepatocyte and biliary distribution via transporters, can also play significant roles in CL H Recent advances in understanding the interplay of metabolism and drug transport for clearance processes have aided in developing the extended clearance model. In this study, we demonstrate proof of concept of a novel two-step assay enabling the measurement of multiple kinetic parameters from a single experiment in plated human primary hepatocytes with and without transporter and cytochrome P450 inhibitors-the hepatocyte uptake and loss assay (HUpLA). HUpLA accurately predicted the CL H of eight of the nine drugs (within twofold of the observed CL H ). Distribution clearances were within threefold of observed literature values in standard uptake and efflux assays. In comparison, the conventional suspension hepatocyte stability assay poorly predicted the CL H The CL H of only two drugs was predicted within twofold of the observed CL H Therefore, HUpLA is advantageous by enabling the measurement of enzymatic and transport processes concurrently within the same system, alleviating the need for applying scaling factors independently. The use of primary human hepatocytes enables physiologically relevant exploration of transporter-enzyme interplay. Most importantly, HUpLA shows promise as a sensitive measure for low-turnover drugs. Further evaluation across different drug characteristics is needed to demonstrate method robustness. SIGNIFICANCE STATEMENT: The hepatocyte uptake and loss assay involves measuring four commonly derived in vitro hepatic clearance endpoints. Since endpoints are generated within a single test system, it blunts experimental error originating from assays otherwise conducted independently. A key advantage is the concept of removing drug-containing media following intracellular drug loading, enabling the measurement of drug reappearance rate in media as well as the measurement of loss of total drug in the test system unencumbered by background quantities of drug in media otherwise present in a conventional assay., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Aim: Characterize the logistical challenges faced by healthcare professionals (HCPs), patients and caregivers during the chimeric antigen receptor T-cell (CAR T) treatment process for non-Hodgkin lymphoma patients. Materials & methods: HCPs in the US and UK experienced with CAR T administration participated in interviews and completed a web-based survey. Results: A total of 133 (80 US, 53 UK) HCPs participated. Two or more logistical challenges were identified by ≥60% of respondents across all stages of the CAR T process. Commonly reported challenges were lengthy waiting periods, administrative and payer-related barriers, limited healthcare capacity, caregiver support and (particularly in the US) patient out-of-pocket costs. Conclusion: The CAR T treatment process presents numerous challenges, highlighting an unmet need for more convenient therapies.

Background: While minoritized populations are less likely to participate in cancer trials, it is unknown whether social determinants of health (SDOH) explain these inequities. Here we identify SDOH factors that contribute to racial/ethnic inequities in clinical trial participation among patients with 22 common cancers., Methods: This retrospective cohort study used electronic health record data (2011-2023) linked to neighborhood (Census tract) data from multiple sources. Patients were followed from diagnosis to clinical study drug receipt (proxy for trial participation), death, or last recorded activity. Associations were assessed using Cox proportional hazards models adjusted for clinical factors (diagnosis year, age, sex, performance status, stage, cancer type). To elucidate which area-level SDOH underlie racial/ethnic inequities, mediation analysis was performed using nonlinear multiple additive regression tree models., Results: This study included 250105 patients (64.7% non-Latinx White, 8.9% non-Latinx Black, 5.2% Latinx). Black and Latinx patients were more likely to live in economically/socially marginalized areas (eg, disproportionately minoritized [measure of segregation], limited English proficiency [LEP], low vehicle ownership) than White patients. Black (3.7%; HR = 0.55 [CI = 0.52-0.60]) and Latinx patients (4.4%; HR = 0.63 [CI = 0.58-0.69]) were less likely to participate in trials than White patients (6.3%). Fewer patients in economically/socially marginalized neighborhoods participated in trials. Mediators explained 62.2% (CI = 49.5%-74.8%) of participation inequities between Black and White patients; area-level SDOH-including segregation (29.9% [CI = 21.2%-38.6%]) and vehicle ownership (11.6% [CI = 7.0%-16.1%])-were the most important mediators. Similarly, Latinx-White participation inequities were mediated (65.1%, [CI = 49.8%-80.3%]) by area-level SDOH such as segregation (39.8% [CI = 28.3%-51.3%]), LEP (11.6%, [CI = 2.8%-20.4%]), and vehicle ownership (9.6% [CI = 5.8%-13.5%])., Conclusions: To improve racial/ethnic diversity in cancer trials, efforts to address barriers related to adverse neighborhood SDOH factors are necessary., (© The Author(s) 2024. Published by Oxford University Press.)

Nanomedicine drug products have reached an unprecedented high in terms of global commercial acceptance and media exposure with the approvals of the mRNA COVID-19 vaccines in 2021. In this paper, we examine the current state of the art for nanomedicine technologies as applied for pharmaceutical products and compare those trends with results from a recent IQ Consortium industry survey on nanomedicine drug products. We find that 1) industry companies continue to push the envelope in terms of new technologies for characterizing their specific drug products, 2) new analytical technologies continue to be utilized by industry to characterize the increasingly complex nanomedicine drug products and 3) alignment and communication are key between industry and regulatory authorities to better understand the regulatory filings that are being submitted. There are many CMC challenges that a company must overcome to successfully file a nanomedicine drug product. In 2022, the FDA Guidance on Drug Products containing Nanomaterials was published, and it provides a roadmap for submission of a nanomedicine drug product. We propose that our paper serves as a complimentary guide providing knowledge on specific CMC issues such as quality attributes, physicochemical characterization methods, excipients, and stability., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Proper and timely characterization of the safety profile of a pharmaceutical product under development is imperative for assessing the overall benefit-risk relationship of the product and for making key development decisions. For ongoing clinical development, a comprehensive and robust safety monitoring and safety signal detection program which is based upon quantitative statistical reasoning is critical. Methods presented here can be applied to safety signal detection and periodic safety monitoring. Various statistical properties, distributions, and models, all utilizing a Bayesian framework are considered and further examined in order to identify robust methods applicable to a broad set of scenarios and situations. Methods developed for incidence counts (including those with under-dispersed distributions) with variable time-at-risk and with underlying constant or non-constant hazard rates, are proposed and compared to traditional methods designed to assess adverse event incidence rates or binomial incidence proportions (which assume an underlying constant hazard rate and subsequent Poisson distribution for modeling event counts).

Aims: In advanced Parkinson's disease (aPD), adequate 24-hour control of OFF-time may not be achievable using oral/transdermal therapies. Clinical trials of foslevodopa/foscarbidopa (LDp/CDP) demonstrate meaningful reductions in OFF-time and OFF-related sleep disturbance in aPD. Previous analyses have only considered direct medical costs: this analysis considers a broader societal perspective (direct non-medical costs, informal care, loss of earnings, productivity and tax)., Methods: Inputs for the societal impact model were taken from a cost-utility model comparing LDp/CDp with best medical treatment (BMT), accepted by the UK National Institute of Health and Care Excellence (NICE). Quintiles of normalized OFF-time across a 16-hour waking day in each treatment group were applied to literature-based estimates for direct medical, non-medical and indirect costs. The resulting state-specific cost estimates were applied to the modelled aPD patient population., Results: The model estimates the potential UK population for LDp/CDp at 17,505. Continuous 24-hour delivery of LDp/CDp results in greater time spent in in OFF-time states 0-1 (0-4 hours of OFF-time/16-hour waking day) vs BMT alone. Net savings if all eligible patients receive LDp/CDp are £79.1M in year 1, £235.4M in year 2, rising to £262.2M in year 3, declining to £222.9M in year 4 and £153.7M in year 5 as disease progresses and efficacy of LDp/CDp declines, Estimated total net savings are £953M after 5 years. Results are robust in scenario analyses (excluding costs of excessive sleepiness, earnings loss, productivity and tax loss)., Limitations: A NICE-accepted model was used as the economic modelling basis for the societal impact model, however, much of the data was derived from Adelphi datasets, with the potential for inconsistent definitions., Conclusion: When considered from a societal perspective, the use of LDp/CDp in aPD patients inadequately controlled on oral therapy, is associated with net healthcare and societal annual savings of over £79.1M vs BMT.

Objectives: The aim was to evaluate the influence of weather parameters on disease activity assessed by Routine Assessment of Patient Index Data (RAPID) scores via a Web-based smartphone application (WebApp). Methods: Correlation of changes of temperature (change of temperature, °C) and air pressure (change of air pressure, hPa) two days prior to and weekly self-assessment of disease activity by RAPID-3 scores over three months. To define background noise and quadrants of weather changes, we defined a central quadrant ± 2 hPa and ± 2° C, called E1. Based on this inner square, four quadrants were defined: A1 = sector left side above with increasing temperature and air pressure (improving weather); B1 = sector right side above; C1 = decreasing temperature and air pressure sector right side down (worsening weather); and D1 = sector left side down. Alterations of RAPID-3 scores analyzed changes in disease activity compared to RAPID-3 scores detected one week in advance. Results: Eighty patients were included in the analysis (median RA duration, 4.5 years; age, 57 years; 59% female). Median disease activity was 2.8 as assessed by DAS 28. In total, 210 time points were analyzed for quadrant A1, 164 for quadrant B1, 160 for quadrant C1, 196 for quadrant D1, and 145 for the inner square E1 were found during follow-up. The middle square E1 was balanced between increasing or decreasing values for RAPID scores. The odds for increasing RAPID scores were 1.33 (95% confidence interval CI: 1.0-1.78) for patients with ameliorating weather conditions which improve or alleviate unfavorable or adverse conditions (A1) compared to 0.98 (CI: 0.67-1.45) for worsening weather (C1) as defined by temperature and air pressure. Conclusions: On average, more patients developed a slight increase of disease activity if they were in the quadrant with increasing temperature and air pressure (improving weather). Thus, no correlation between the worsening of the weather and changing RAPID-3 scores was found.

By evaluating published emulations of oncology RCTs studies in which both the active and comparator groups are sourced from RWD and target trial results are available for benchmarking, this systematic review aims to gain insight into factors related to emulation performance. Thirteen oncology emulation studies using various types of RWD were identified through an online database search of PubMed through 2022. Based on the ROBINS-I tool, most studies (N=8) had a serious risk of overall bias driven by risk of bias from confounding. Approximately half of the studies (N=6) fully proxied the RCT entry criteria. Of 11 RWD studies that provided sufficient detail to quantify emulation performance, the emulation HR estimate fell within the 95% CI of the trial estimate in 9 of the studies. There were no clear trends between risk of bias or degree to which the entry criteria were proxied and emulation performance. Findings may have been influenced by publication bias and researcher degrees of freedom, as only one emulation study pre-registered its protocol. Tools for comprehensively characterizing factors that affect emulation performance, including the real-world clinical context as it relates to the RCT research question, are needed to evaluate the feasibility of a RCT emulation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To estimate the number needed to treat and cost per additional responder for atogepant and rimegepant versus placebo for the preventive treatment of episodic migraine (EM) in the United States., Background: Migraine has an enormous impact on a person's daily activities and quality of life, and results in significant clinical and economic burden to both individuals and society. It is important to understand the comparative efficacy and economic value of oral calcitonin gene-related peptide receptor antagonists (gepants) for preventive treatment of EM. Currently, atogepant and rimegepant are US Food and Drug Administration approved for preventive treatment of migraine (rimegepant for EM and atogepant for EM and for chronic migraine). In the absence of head-to-head trials, we utilized an indirect treatment comparison on efficacy data from clinical trials conducted for the preventive treatment of EM. We estimated number needed to treat, a valuable metric used in clinical practice to compare treatment efficacy, and cost per additional responder, which can be used to establish the cost effectiveness of a treatment., Methods: An indirect treatment comparison was conducted to compare the efficacy of atogepant 60 mg once daily and rimegepant 75 mg once every other day as preventive treatments for EM using published data from the registrational trials of atogepant (ADVANCE) and rimegepant (BHV3000-305). The efficacy outcome of interest was ≥50% reduction from baseline in mean monthly migraine/headache days (≥50% responder rate), which was variably defined for a base case and two scenario analyses. Number needed to treat and cost per additional responder versus placebo were calculated and compared between both treatments (weeks 9-12 in the base case analysis; weeks 1-12 and 9-12 for atogepant and during weeks 9-12 for rimegepant in the scenario analyses)., Results: In the base case analysis, ≥50% responder rates were 64.9% (95% confidence interval [CI], 53.9-74.5) for atogepant and 51.8% (95% CI, 42.9-60.6) for rimegepant, compared to 44.1% (95% CI, 39.4-49.0) for placebo. The median number needed to treat versus placebo in the base case scenario was 4.8 (95% CI, 3.1-9.0) for atogepant compared to 13.0 (95% CI, 5.9-75.1) for rimegepant. The cost per additional responder versus placebo in the base case scenario was estimated to be $15,823 (95% CI, $11,079-$29,516) for atogepant compared to $73,029 (95% CI, $32,901-$422,104) for rimegepant. Results of the two scenario analyses were consistent with the base case analysis., Conclusions: Atogepant had substantially lower numbers needed to treat and costs per additional responder versus placebo than rimegepant for the preventive treatment of EM across all evaluated scenarios. These analyses suggest that atogepant may be more cost effective than rimegepant for the preventive treatment of EM. Limitations include differences in inclusion/exclusion criteria and in reporting of the ≥50% responder rates between trials., (© 2024 American Headache Society.)

Background and Aims: Corticosteroids are widely used in managing inflammatory bowel disease [IBD]. While adverse events [AEs] of corticosteroids are well recognised, current understanding of corticosteroid-related AE burden in IBD remains incomplete., Methods: AE reports for prednisone/prednisolone and budesonide were extracted from the Food and Drug Administration Adverse Event Reporting System [FAERS] and VigiBase databases. Total and frequently reported AEs were tabulated, and AEs of special interest were compared with reports for all drugs using proportional reporting ratio criteria. Database reports were compared with AEs reported in a patient survey capturing corticosteroid exposure and AE recall., Results: In FAERS and VigiBase, 344,140 and 42,836 AEs were reported, respectively, in patients with IBD; among these, 10,157 [3.0%] and 11,391 [26.6%], respectively, were related to prednisone/prednisolone or budesonide. AEs associated with corticosteroid use in IBD increased over time. Adrenal insufficiency, Cushingoid complications, osteonecrosis, osteoporosis, diabetes and pancreatitis were disproportionately reported for corticosteroids. Among 9229 patients who responded to the survey, 6434 [69.7%] reported corticosteroid exposure. AEs were more frequently recalled by patients exposed to prednisone [61.9%] vs budesonide [27.4%; p = 0.0001]. The most commonly recalled AEs differed from those reported in the pharmacovigilance databases and included weight gain, sleep problems, mood disturbance and skin changes. Younger patients and those with mental health disorders were more likely to recall suicidal thoughts/attempts., Conclusions: AEs associated with IBD-related corticosteroid use were frequent. Patients reported AEs affecting quality of life, while clinicians disproportionately reported AEs based on objective diagnostic criteria., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Conventional solid oral dosage form development is not typically challenged by reliance on an amorphous drug substance as a direct ingredient in the drug product, as this may result in product development hurdles arising from process design and scale-up, control of physical quality attributes, drug product processability and stability. Here, we present the Chemistry, Manufacturing and Controls development journey behind the successful commercialization of an amorphous drug substance, Elagolix Sodium, a first-in-class, orally active gonadotropin-releasing hormone antagonist. The reason behind the lack of crystalline state was assessed via Molecular Dynamics (MD) at the molecular and inter-molecular level, revealing barriers for nucleation due to prevalence of intra-molecular hydrogen bond, repulsive interactions between active pharmaceutical ingredient (API) molecules and strong solvation effects. To provide a foundational basis for the design of the API manufacturing process, we modeled the solvent-induced plasticization behavior experimentally and computationally via MD for insights into molecular mobility. In addition, we applied material science tetrahedron concepts to link API porosity to drug product tablet compressibility. Finally, we designed the API isolation process, incorporating computational fluid dynamics modeling in the design of an impinging jet mixer for precipitation and solvent-dependent glass transition relationships in the cake wash, blow-down and drying process, to enable the consistent manufacture of a porous, non-sintered amorphous API powder that is suitable for robust drug product manufacturing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Protein A (PA) is a bacterial cell wall component of Staphylococcus aureus whose function is to bind to Immunoglobulin G (IgG). Given its ability to bind IgG as well as its stability and resistance to harsh acidic and basic cleaning conditions, it is commonly used in the affinity chromotography purification of biotherapeutics. This use can result in levels of PA being present in a drug product and subsequent patient exposure. Interestingly, PA was previously evaluated in clinical trials as well as supporting nonclinical studies, resulting in a database that enables the derivation of a health-based exposure limit (HBEL). Given the widespread use of PA in the pharmaceutical industry, the IQ DruSafe Impurities Safety Working Group (WG) evaluated the available information with the purpose of establishing a harmonized parenteral HBEL for PA. Based on this thorough, collaborative evaluation of nonclinical and clinical data available for PA, a parenteral HBEL of 1.2 μg/kg/dose (60 μg/dose for a 50 kg individual) is expected to be health protective for patients when it is present as an impurity in a biotherapeutic., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: The term gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features could not be established., Methods: We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization., Results: Median overall survival (OS) was 15.5 months (interquartile range, 10.9-27.7) with a 2-year survival rate of 28%. Histopathological grading correlated significantly with median OS: CNS WHO grade II: 47.8 months (25.2-55.7); grade III: 15.9 months (11.4-26.3); grade IV: 10.4 months (8.8-14.4). By DNA methylation profiling (n = 49), most tumors were classified as pediatric-type diffuse high-grade glioma (pedHGG), H3-/IDH-wild-type (n = 31/49, 63.3%) with enriched subclasses pedHGG&#95;RTK2 (n = 19), pedHGG&#95;A/B (n = 6), and pedHGG&#95;MYCN (n = 5), but only one pedHGG&#95;RTK1 case. Within the pedHGG, H3-/IDH-wild-type subgroup, recurrent alterations in EGFR (n = 10) and BCOR (n = 9) were identified. Additionally, we observed structural aberrations in chromosome 6 in 16/49 tumors (32.7%) across tumor types. In the pedHGG, H3-/IDH-wild-type subgroup TP53 alterations had a significant negative effect on OS., Conclusions: Contrary to previous studies, our representative pediatric GC study provides evidence that GC has a strong predilection to arise on the background of specific molecular features (especially pedHGG&#95;RTK2, pedHGG&#95;A/B, EGFR and BCOR mutations, chromosome 6 rearrangements)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Purpose: The concept of a Design Space (DSp) was introduced in ICH Q8 as a tool within the quality-by-design (QbD) approach to pharmaceutical development with the intent of being globally applicable. However, there appears to be variance in the regulatory agency expectations in pharmaceutical product filing and implementation of DSp. This paper presents some of the current industry perspective on design space., Methods: The Utilization of Design Space for Filings (UDSpF) Working Group in the Innovation and Quality (IQ) Consortium conducted a survey to establish a baseline for the current understanding of DSp among IQ member companies and assess the similarities and/or differences in strategies when filing a DSp. The survey focused on how IQ member companies approach DSp development, the primary drivers for the DSp, the presentation of the DSp in the filing, DSp verification and the benefits and flexibility anticipated and/or realized., Results: A total of 14 responses were received and analyzed representing a small sample size but a large proportion of the innovator industry/large pharmaceutical companies. The survey results revealed that DSp is not yet a commonplace for small molecule drug products and may not even be utilized as much in large molecule drug products. The benefits of DSp, with respect to enhanced process understanding, are well understood by the sponsors; however, the benefits of filed DSp with respect to manufacturing flexibility are not fully realized in the commercial lifecycle of the product. There are also challenges in gaining consistent buy-in/value proposition for DSp among cross-functional teams within organizations., Conclusions: There are still gaps in design space implementation for its full benefit in the pharmaceutical industry. The WG has presented a unified view from member companies on the approach to DSp considering when/where the DSp experiments are conducted and on the extent of the DSp development proposed in a dossier., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: We evaluated the association of achieving endoscopic outcomes at week 12 of induction with improvements in clinical outcomes and quality of life (QoL) at week 52 of maintenance in patients with moderately to severely active Crohn's disease (CD) treated with upadacitinib (UPA)., Methods: This post hoc analysis evaluated data from 2 phase 3 induction trials (NCT03345836 and NCT03345849) and 1 maintenance (NCT03345823) trial. Clinical responders to 12-week induction therapy with UPA who also received 52-week maintenance treatment with UPA were included. Endoscopic response, remission, healing, and ulcer-free endoscopy were assessed at week 12. Meaningful improvements in clinical and QoL outcomes were evaluated at week 52., Results: A significantly greater proportion of patients who achieved an endoscopic response at the end of induction, compared with patients who did not, attained Crohn's Disease Activity Index (CDAI) remission (52.0% vs 34.6%; P ≤ .01), corticosteroid-free CDAI remission (50.0% vs 30.9%), Inflammatory Bowel Disease Questionnaire remission (52.6% vs 30.3%), and meaningful improvements in Functional Assessment of Chronic Illness Therapy-Fatigue response (46.7% vs 25.9%), overall work impairment (47.1% vs 26.5%), and daily activity impairment (53.3% vs 34.1%) (all P < .05) at week 52. Similar findings were observed for patients who achieved endoscopic remission, endoscopic healing, and ulcer-free endoscopy at the end of induction vs those who did not., Conclusions: Early improvement in endoscopic outcomes after UPA induction treatment was associated with long-term meaningful improvements in clinical outcomes and QoL in patients with CD., Clinical Registration Number: U-EXCEED induction trial (NCT03345836), U-EXCEL induction trial (NCT03345849), and U-ENDURE maintenance trial (NCT03345823)., (© 2024 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Background: Black women are disproportionately affected by overweight and obesity. One theory that may have utility in increasing the amount of exercise among Black women is self-determination theory, a psychology-based theory commonly used to investigate motivation in the context of exercise. The objective of this study was to determine whether motivation towards exercise behavior differs between younger and older Black women., Methods: A cross-sectional study was conducted by administering a survey to Black women in the Midwestern United States to elicit factors which may impact their motivation to exercise. The survey consisted of questions to gather sociodemographic information as well as responses to the Behavioral Regulations in Exercise Questionnaire (BREQ-2). Responses on the BREQ-2 were utilized to derive the Relative Autonomy Index (RAI) which is a direct measure of self-determination that provides insight into the extent of an individual's motivation to exercise. Multiple linear regression was utilized to determine if age was predictive of relative RAI scores after adjusting for marital status and receipt of a memorable message regarding health., Results: Mean RAI scores among respondents at least 40 years old were significantly higher in comparison to the RAI among respondents younger than 40. When adjusting for marital status and receipt of a memorable message regarding health, women at least 40 had a mean RAI score approximately 4.2 points higher than those under age 40. Women at least 40 years of age also had significantly higher scores on the identified regulation and intrinsic regulation subscales of the BREQ-2 questionnaire when compared to women younger than 40 after adjusting for marital status and recalling a memorable message related to health., Conclusion: These findings suggest that exercise motivations differ among age groups of Black women. Additionally, these results highlight the importance of understanding exercise motivations to further improve health outcomes., (© 2024. W. Montague Cobb-NMA Health Institute.)

Objective: To estimate the economic impact for the society, generated as a consequence of the onset of loss of vision and irreversible legal blindness, for the main ophthalmologic diseases in Spain: glaucoma, diabetic retinopathy (DR), diabetic macular edema (DME), age-related macular degeneration (AMD) and high myopia (HM)., Methods: A cost analysis model was developed to estimate the economic burden of glaucoma, DR, DME, AMD and HM over a 10-year time horizon (2021-2030), from a societal perspective in Spain. The epidemiological and economic parameters used in the model were obtained through a literature review. Prevalence, incidence, and progression stages were used to establish the epidemiological flows. Annual costs per patient from publications were included and classified into direct healthcare, direct non-healthcare and indirect costs. Costs from other countries were converted based on purchasing-power-parity (€EUR, PPP). Epidemiological parameters about population and cost results were validated by a panel of experts. All costs were adjusted to euros, 2021 (€, 2021), and using the Consumer Price Index (CPI) of the last 10 years, extrapolated to 2030 euros (€, 2030)., Results: It was estimated that the total population of patients with the main diseases pathologies (glaucoma, DR, DME, AMD and HM) will increase to 7.99 million patients by 2030, representing an increase of 103%. The total cost by 2030 of all pathologies would amount to 99.8 billion euros. Direct non-healthcare costs account for the largest item (44%), followed by loss of productivity costs (38%), and direct healthcare costs (18%). The pathologies with the highest cumulative costs will be glaucoma (€33.6 billion) and DME (€19.8 billion).The greatest increment costs compared to 2021 will likely be generated by pathologies related to diabetes mellitus, such as DR (703%) and DME (317%)., Conclusions: Knowing the costs associated with the pathologies that generate loss of vision and irreversible legal blindness is essential to understand the socioeconomic impact associated with these pathologies. Furthermore, the high cost of treating these diseases makes necessary to coordinate efforts between administrations, together with the support of patient associations, to meet their needs., (© 2024. The Author(s).)

The epidermal growth factor receptor (EGFR) protein is highly expressed in a range of malignancies. Although therapeutic interventions directed toward EGFR have yielded therapeutic responses in cancer patients, side effects are common because of normal-tissue expression of wild-type EGFR. We developed a novel tumor-specific anti-EGFR chimeric antibody ch806 labeled with 225 Ac and evaluated its in vitro properties and therapeutic efficacy in murine models of glioblastoma and colorectal cancer. Methods: 225 Ac-ch806 was prepared using different chelators, yielding [ 225 Ac]Ac-macropa-tzPEG 3 Sq-ch806 and [ 225 Ac]Ac-DOTA-dhPzPEG 4 -ch806. Radiochemical yield, purity, apparent specific activity, and serum stability of 225 Ac-ch806 were quantified. In vitro cell killing effect was examined. The biodistribution and therapeutic efficacy of 225 Ac-ch806 were investigated in mice with U87MG.de2-7 and DiFi tumors. Pharmacodynamic analysis of tumors after therapy was performed, including DNA double-strand break immunofluorescence of γH2AX, as well as immunohistochemistry for proliferation, cell cycle arrest, and apoptosis. Results: [ 225 Ac]Ac-macropa-tzPEG 3 Sq-ch806 surpassed [ 225 Ac]Ac-DOTA-dhPzPEG 4 -ch806 in radiochemical yield, purity, apparent specific activity, and serum stability. [ 225 Ac]Ac-macropa-tzPEG 3 Sq-ch806 was therefore used for both in vitro and in vivo studies. It displayed a significant, specific, and dose-dependent in vitro cell-killing effect in U87MG.de2-7 cells. 225 Ac-ch806 also displayed high tumor uptake and minimal uptake in normal tissues. 225 Ac-ch806 significantly inhibited tumor growth and prolonged survival in both U87MG.de2-7 and DiFi models. Enhanced γH2AX staining was observed in 225 Ac-ch806-treated tumors compared with controls. Reduced Ki-67 expression was evident in all 225 Ac-ch806-treated tumors. Increased expression of p21 and cleaved caspase 3 was shown in U87MG.de2-7 and DiFi tumors treated with 225 Ac-ch806. Conclusion: In glioblastoma and colorectal tumor models, 225 Ac-ch806 significantly inhibited tumor growth via induction of double-strand breaks, thereby constraining cancer cell proliferation while inducing cell cycle arrest and apoptosis. These findings underscore the potential clinical applicability of 225 Ac-ch806 as a potential therapy for EGFR-expressing solid tumors., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction characterized by abdominal pain and altered bowel habits, with patient-perceived dissatisfaction of treatment symptom control. We assessed disease burden, satisfaction with medication use, and impact on activities, in participants with IBS with constipation (IBS-C) and diarrhea (IBS-D)., Methods: This study assessed data from a large, United States survey of adults querying demographics, comorbid conditions, quality of life, medication use, satisfaction with symptom control, and work productivity. Participants were grouped into the IBS-C or IBS-D cohort if they met Rome IV criteria, with controls matched 1:1 according to age, sex, race, region, and Charlson Comorbidity Index score. All data were self-reported., Key Results: Nine hundred and ten participants with IBS-C and 669 with IBS-D were matched to controls. The most reported symptoms were abdominal discomfort for IBS-C and abdominal pain and abdominal discomfort for IBS-D. Among the IBS-C and IBS-D cohorts, 74.2% and 65.9%, respectively, took prescription and/or over-the-counter medication for their symptoms. Respondents were more dissatisfied than satisfied with control of their symptoms. Respondents taking prescription medication(s) with or without over-the-counter medication(s) reported better symptom control than respondents only taking over-the-counter medications (p < 0.001). There was significantly higher mean presenteeism, work productivity loss, and daily activity impairment (p < 0.001 for all) in respondents with IBS compared with controls., Conclusions and Inferences: This study provides insight into respondents' experiences of IBS symptoms, including the impact on daily activity, as well as satisfaction with control of symptoms and prescription and over-the-counter medications., (© 2024 The Author(s). Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Reversible self-association (RSA) of therapeutic proteins presents major challenges in the development of high-concentration formulations, especially those intended for subcutaneous administration. Understanding self-association mechanisms is therefore critical to the design and selection of candidates with acceptable developability to advance to clinical trials. The combination of experiments and in silico modeling presents a powerful tool to elucidate the interface of self-association. RSA of monoclonal antibodies has been studied extensively under different solution conditions and have been shown to involve interactions for both the antigen-binding fragment and the crystallizable fragment. Novel modalities such as bispecific antibodies, antigen-binding fragments, single-chain-variable fragments, and diabodies constitute a fast-growing class of antibody-based therapeutics that have unique physiochemical properties compared to monoclonal antibodies. In this study, the RSA interface of a diabody-interleukin 22 fusion protein (FP-1) was studied using hydrogen-deuterium exchange coupled with mass spectrometry (HDX-MS) in combination with in silico modeling. Taken together, the results show that a complex solution behavior underlies the self-association of FP-1 and that the interface thereof can be attributed to a specific segment in the variable light chain of the diabody. These findings also demonstrate that the combination of HDX-MS with in silico modeling is a powerful tool to guide the design and candidate selection of novel biotherapeutic modalities.

Background: OnabotulinumtoxinA (onabotA), is assumed to achieve its therapeutic effect in migraine through blocking activation of unmyelinated meningeal nociceptors and their downstream communications with central dura-sensitive trigeminovascular neurons in the spinal trigeminal nucleus (SPV). The present study investigated the mechanism of action of onabotA by assessing its effect on activation and sensitization of dura-sensitive neurons in the SPV by cortical spreading depression (CSD). It is a follow up to our recent study on onabotA effects on activation and sensitization of peripheral trigeminovascular neurons., Methods: In anesthetized male and female rats, single-unit recordings were used to assess effects of extracranial injections of onabotA (five injections, one unit each, diluted in 5 μl of saline were made along the lambdoid (two injection sites) and sagittal (two injection sites) suture) vs. vehicle on CSD-induced activation and sensitization of high-threshold (HT) and wide-dynamic range (WDR) dura-sensitive neurons in the SPV., Results: Single cell analysis of onabotA pretreatment effects on CSD-induced activation and sensitization of central trigeminovascular neurons in the SPV revealed the ability of this neurotoxin to prevent activation and sensitization of WDR neurons (13/20 (65%) vs. 4/16 (25%) activated neurons in the control vs. treated groups, p  = 0.022, Fisher's exact). By contrast, onabotA pretreatment effects on CSD-induced activation and sensitization of HT neurons had no effect on their activation (12/18 (67%) vs. 4/7 (36%) activated neurons in the control vs. treated groups, p  = 0.14, Fisher's exact). Regarding sensitization, we found that onabotA pretreatment prevented the enhanced responses to mechanical stimulation of the skin (i.e. responses reflecting central sensitization) in both WDR and HT neurons. In control but not treated WDR neurons, responses to brush ( p =  0.004 vs. p =  0.007), pressure ( p  = 0.002 vs. p  = 0.79) and pinch ( p  = 0.007 vs. 0.79) increased significantly two hours after CSD. Similarly, in control but not treated HT neurons, responses to brush ( p =  0.002 vs. p =  0.79), pressure ( p  = 0.002 vs. p  = 0.72) and pinch ( p  = 0.0006 vs. p  = 0.28) increased significantly two hours after CSD. Unexpectedly, onabotA pretreatment prevented the enhanced responses of both WDR and HT neurons to mechanical stimulation of the dura (commonly reflecting peripheral sensitization). In control vs. treated WDR and HT neurons, responses to dural stimulation were enhanced in 70 vs. 25% ( p  = 0.017) and 78 vs. 27% ( p  = 0.017), respectively., Conclusions: The ability of onabotA to prevent activation and sensitization of WDR neurons is attributed to its preferential inhibitory effects on unmyelinated C-fibers. The inability of onabotA to prevent activation of HT neurons is attributed to its less extensive inhibitory effects on the thinly myelinated Aδ-fibers. These findings provide further pre-clinical evidence about differences and potentially complementary mechanisms of action of onabotA and calcitonin gene-related peptide-signaling neutralizing drugs., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RB is the John Hedley-Whyte Professor of Anesthesia and Neuroscience at the Beth Israel Deaconess Medical Center and Harvard Medical School. He has received research support from the NIH: R01 NS094198-01A1, R37 NS079678, R01NS095655, R01 NS104296, R21 NS106345, Allergan, Teva, Dr Ready, Eli Lilly, Trigemina and the Migraine Research Foundation. He is a reviewer for NINDS, holds stock options in AllayLamp and Percept; serves as consultant, advisory board member, or has received honoraria from: Alder, Allergan, Biohaven, Dr Reddy's Laboratory, Eli Lilly, GlaxoSmithKline, Merck, Teva and Trigemina. CME fees from Healthlogix, Medlogix, WebMD/Medscape, and Patents 9061025, 11732265.1, 10806890, US2021-0015908, WO21007165, US2021-0128724, WO210054RBr, BD, AMA and MFB are employees of Allergan, an AbbVie Company.The other authors declare that they have no conflicts of interest.

Background: OnabotulinumtoxinA is an injectable product that was introduced into medicine in the 1970s and has been the subject of thousands of clinical and nonclinical publications., Objective: To review the data related to the versatility of onabotulinumtoxinA in medical aesthetics., Methods: PubMed was searched to identify literature evaluating the effects of onabotulinumtoxinA, with preference given to randomized, placebo-controlled trials and safety meta-analyses., Results: OnabotulinumtoxinA is effective and safe across multiple facial indications, racial and ethnic groups, age groups, genders, and facial line severities. Patient-reported outcomes have been prioritized in aesthetic clinical trials and indicate high patient satisfaction and appearance-related psychological outcomes. Integrated safety meta-analysis and immunogenicity analyses have documented acceptable adverse event rates and low immunogenicity of onabotulinumtoxinA., Conclusion: OnabotulinumtoxinA is a versatile aesthetic product supported by a strong literature base and positive physician and patient-reported outcomes that reflect a meaningful impact on patient's quality of life., (Copyright © 2024 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: This study compared the clinical effectiveness of switching from tumor necrosis factor inhibitor (TNFi) to upadacitinib (TNFi-UPA), another TNFi (TNFi-TNFi), or an advanced therapy with another mechanism of action (TNFi-other MOA) in patients with rheumatoid arthritis (RA)., Methods: Data were drawn from the Adelphi RA Disease Specific Programme™, a cross-sectional survey administered to rheumatologists and their consulting patients in Germany, France, Italy, Spain, the UK, Japan, Canada, and the USA from May 2021 to January 2022. Patients who switched treatment from an initial TNFi were stratified by subsequent therapy of interest: TNFi-UPA, TNFi-TNFi, or TNFi-other MOA. Physician-reported clinical outcomes including disease activity (with formal DAS28 scoring available for 29% of patients) categorized as remission, low/moderate/high disease activity, as well as pain were recorded at initiation of current treatment and ≥ 6 months from treatment switch. Fatigue and treatment adherence were measured ≥ 6 months from treatment switch. Inverse-probability-weighted regression adjustment compared outcomes by subsequent class of therapy: TNFi-UPA versus TNFi-TNFi, or TNFi-UPA versus TNFi-other MOA., Results: Of 503 patients who switched from their first TNFi, 261 were in TNFi-UPA, 128 in TNFi-TNFi, and 114 in TNFi-other MOA groups. At the time of switch, most patients had moderate/high disease activity (TNFi-UPA: 73%; TNFi-TNFi: 52%; TNFi-other MOA: 60%). After adjustment for differences in characteristics at point of switch, patients in TNFi-UPA group (n = 261) were significantly more likely to achieve physician-reported remission (67.7% vs. 40.3%; p = 0.0015), no pain (55.7% vs. 25.4%; p = 0.0007), and complete adherence (60.0% vs. 34.2%; p = 0.0049) compared with patients in TNFi-TNFi group (n = 121). Similar findings were observed for TNFi-UPA versus TNFi-other MOA groups (n = 111)., Conclusion: Patients who switched from TNFi to UPA had significantly better clinical outcomes of remission, no pain, and complete adherence than those who cycled TNFi or switched to another MOA., (© 2024. The Author(s).)

Electrophilic halogenation is a widely used tool employed by medicinal chemists to either pre-functionalize molecules for further diversity or incorporate a halogen atom into drugs or drug-like compounds to solve metabolic problems or modulate off-target effects. Current methods to increase the power of halogenation rely on either the invention of new reagents or activating commercially available reagents with various additives such as Lewis or Brønsted acids, Lewis bases and hydrogen-bonding activators. There is a high demand for new reagents that can halogenate otherwise unreactive compounds under mild conditions. Here we report the invention of a class of halogenating reagents based on anomeric amides, taking advantage of the energy stored in the pyramidalized nitrogen of N-X anomeric amides as a driving force. These robust halogenating methods are compatible with a variety of functional groups and heterocycles, as exemplified on over 50 compounds (including 13 gram-scale examples and 1 flow chemistry scale-up)., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

SERENE CD (NCT02065570) evaluated whether a higher adalimumab induction dose would improve patients with Crohn disease response and suggested a flat dose-response relationship for efficacy in the induction study. We investigated exposure-response relationships in induction and maintenance studies considering patients' baseline characteristics. Adalimumab exposures were simulated using the established population pharmacokinetic model. Efficacy end points (clinical remission/endoscopic response) at Weeks 4, 12, and 56 were evaluated in exposure-response analyses using multivariable logistic regression. Analyses showed an increasing trend with heterogeneity between induction regimens, which suggested that average concentration has an impact on coprimary efficacy end points within each group, but data did not fit a single-response curve. Although higher concentrations within arms were associated with improved outcomes, increasing the concentration through a higher induction dose was not associated with increasing clinical remission/endoscopic response at Week 4/12. A model including inverse effective clearance eliminated heterogeneity and described trends across induction regimens with a single curve. In the maintenance study, the response rates at Week 56 showed no heterogeneity. In the induction study, patients with lower effective adalimumab clearance responded better, whereas in the maintenance study average concentration drove primary efficacy end points at Week 56. Research extending these findings to other indications is needed., (© 2024, The American College of Clinical Pharmacology.)

Introduction: Individuals living with Crohn's disease (CD) experience burdensome symptoms. As such, it is important to measure CD symptom severity in clinical research. The goal of this study was to evaluate the content validity, psychometric performance, and score interpretability of a new patient-reported instrument, the Crohn's Symptom Severity (CSS) questionnaire, among adolescents and adults with moderately to severely active CD., Methods: Cognitive debriefing interviews (N = 30; n = 20 adults, n = 10 adolescents) were conducted to evaluate the content validity of the CSS. Additionally, the CSS scores were evaluated for reliability and validity using data from a phase 3 randomized clinical trial of risankizumab (NCT03105128; N = 850). Meaningful within-patient change (MWPC) thresholds were estimated using anchor-based methods., Results: All interview participants (n = 30/30, 100.00%) reported the CSS was easy to complete and most participants (n = 28/29, 96.55%) reported that the CSS was relevant to their experience of CD. Among the clinical trial subjects (N = 850) the following was found for the CSS: mostly acceptable item-total correlations (0.26-0.79); weak to moderate inter-item correlations (r = 0.07-0.57), good internal consistency (Cronbach's α = 0.76-0.87); intraclass correlation coefficients ranged from 0.48 to 0.70, not consistently exceeding the acceptable range for test-retest reliability (0.70); acceptable convergent validity and known-groups results; and demonstrated sensitivity to change. Analyses supported an MWPC estimate of 6-11 points., Conclusions: This study supports use of the CSS for measuring CD symptoms and sleep impact among adolescents and adults aged 16 and older with moderately to severely active CD in clinical research., Trial Registration: NCT03105128 (registration date 4 April 2017)., (© 2024. The Author(s).)

SERENE UC (NCT02065622) evaluated whether a higher adalimumab induction regimen improved patients with ulcerative colitis (UC) response, but a flat dose-response relationship was found in the induction study. We investigated exposure-response (ER) relationships in induction and maintenance studies considering patients' baseline characteristics. Adalimumab exposures were simulated using the established population pharmacokinetic model. Multivariable logistic regressions were used to assess the efficacy endpoints (clinical remission, endoscopic remission, endoscopic improvement) at weeks 8 and 52. In the induction study, an increasing ER trend with heterogeneity between induction regimens was shown, suggesting average concentration (C avg ) had a significant impact on primary efficacy endpoints within each group. However, data were not described by a single ER curve. Using inverse effective clearance as the exposure metric described trends across induction regimens with a single curve. Patients with inherently lower effective adalimumab clearance responded better. The patient response rates at week 52 showed no heterogeneity. A short-term increase in adalimumab dose did not drive better responses for induction, and apparent ER relationships were better explained by patient-inherent lower clearance. Conversely, during maintenance up to week 52, increasing the concentration via dose translated to better responses more robustly. The ER findings for SERENE UC were consistent with SERENE CD., (© 2024, The American College of Clinical Pharmacology.)

Previous studies have shown that pharmaceutical agents such as lipoic acid have the ability to soften the lens, presenting a promising avenue for treating presbyopia. One obstacle encountered in the preclinical stage of such agents is the need for precise measurements of lens elasticity in experimental models. This study aimed to evaluate the effects of 25-hydroxycholesterol, lipoic acid, and obeticholic acid on the viscoelastic properties of mouse lenses using a custom-built elastometer system. Data were acquired on lenses from C57BL/6J female mice from two age groups: young (age: 8-10 weeks) and old (age: 32-43 weeks). OD lenses were used as the control and OS lenses were treated. Control lenses were immersed in Dulbecco's Modified Eagle Medium (DMEM) and treatment lenses were immersed in a compound solution containing 25-hydroxycholesterol (5 young and 5 old), lipoic acid at 2.35 mM (5 young and 5 old), lipoic acid at 0.66 mM (5 old), or obeticholic acid (5 old) at 37 °C for 18 h. After treatment, the mouse lenses were placed in a DMEM-filled chamber within a custom-built elastometer system that recorded the load and lens shape as the lens was compressed by 600 μm at a speed of 50 μm/s. The load was continuously recorded during compression and during stress-relaxation. The compression phase was fit with a linear function to quantify lens stiffness. The stress-relaxation phase was fit with a 3-term exponential relaxation model providing relaxation time constants (t 1 , t 2 , t 3 ), and equilibrium load. The lens stiffness, time constants and equilibrium load were compared for the control and treated groups. Results revealed an increase in stiffness with age for the control group (young: 1.16 ± 0.11 g/mm, old: 1.29 ± 0.14 g/mm) and relaxation time constants decreased with age (young: t 1  = 221.9 ± 29.0 s, t 2  = 24.7 ± 3.8 s, t 3  = 3.12 ± 0.87 s, old: t 1  = 183.0 ± 22.0 s, t 2  = 20.6 ± 2.6 s and t 3  = 2.24 ± 0.43 s). Among the compounds tested, only 25-hydroxycholesterol produced statistically significant changes in the lens stiffness, relaxation time constants, and equilibrium load. In conclusion, older mouse lenses are stiffer and less viscous than young mouse lenses. Notably, no significant change in lens stiffness was observed following treatment with lipoic acid, contrary to previous findings., Competing Interests: Declaration of competing interest The research described in this project was funded in part by AbbVie. S. Cabrera-Ghayouri and M. Dibas are employees of AbbVie., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: ABBV-184, a novel survivin peptide-targeting T-cell receptor (TCR)/anti-CD3 bispecific protein, demonstrated preclinical T-cell activation and cytotoxicity toward HLA-A2:01-positive tumor lines. This first-in-human trial evaluated ABBV-184 monotherapy in patients with acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC)., Research Design and Methods: This phase 1 multicenter, open-label, dose escalation trial (NCT04272203) enrolled adult patients with relapsed/refractory AML or NSCLC with an HLA-A2:01 restricted genotype. Patients received ABBV-184 at 0.07 ug/kg initially, with 2- to 3-fold dose increases. The primary objective was determining the ABBV-184 recommended phase 2 dose. Secondary objectives included safety, tolerability, pharmacokinetics, and immunogenicity assessments., Results: Fifteen patients enrolled in the dose escalation (8 AML and 7 NSCLC). ABBV-184 doses ranged from 0.07 mg/kg-0.7 µg/kg, with a half-life of approximately 13-29 hours. Transient cytokine increases were observed at all dose levels, and in patients with NSCLC, transient peripheral blood lymphocyte decreases were observed. The most frequently reported treatment-emergent adverse events (TEAEs) were anemia, diarrhea, and headache. Grade 1-2 infusion-related reaction (IRR) and cytokine release syndrome (CRS) TEAEs were reported., Conclusions: ABBV-184 was well tolerated and demonstrated preliminary evidence of CD3 engagement with transient cytokine increases and peripheral lymphocyte decreases., Clinical Trial Registration: NCT04272203.

Data from phase IIb/III and phase III studies were used to characterize the population pharmacokinetics of risankizumab and its exposure-response relationships for efficacy and safety in ulcerative colitis (UC) patients. A two-compartment model with first-order absorption and elimination accurately described risankizumab pharmacokinetics. Although certain covariates, namely, body weight, serum albumin, fecal calprotectin, sex, corticosteroid use, advanced therapy inadequate response, and pancolitis, were statistically correlated with risankizumab clearance, their impact on exposure was not clinically meaningful for efficacy or safety. Phase II exposure-response analyses demonstrated that the 1,200 mg intravenous (IV) induction dose at Weeks 0, 4, and 8 achieved near maximal response for all efficacy end points, with suboptimal efficacy from the 600 mg and little added benefit from the 1,800 mg regimens, justifying 1,200 mg IV as the induction dose in the phase III study. Phase III exposure-response analyses for efficacy during induction showed statistically significant exposure-response relationships at Week 12 following 1,200 mg IV at Weeks 0, 4, and 8, in line with phase IIb results. Exposure-response analyses for maintenance demonstrated modest improvement in Week 52 efficacy when increasing the subcutaneous dose from 180 mg to 360 mg with largely overlapping confidence intervals. Exposure-response analyses for safety indicated no apparent exposure-dependent safety events over the induction or maintenance treatment. Based on these results, the recommended dosing regimen for risankizumab in UC patients is 1,200 mg IV at Weeks 0, 4, and 8, followed by 180 mg or 360 mg subcutaneously at Week 12 and every 8 weeks thereafter., (© 2024 AbbVie Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The landscape of oncology drug development has witnessed remarkable advancements over the last few decades, significantly improving clinical outcomes and quality of life for patients with cancer. Project Optimus, introduced by the U.S. Food and Drug Administration, stands as a groundbreaking endeavor to reform dose selection of oncology drugs, presenting both opportunities and challenges for the field. To address complex dose optimization challenges, an Oncology Dose Optimization IQ Working Group was created to characterize current practices, provide recommendations for improvement, develop a clinical toolkit, and engage Health Authorities. Historically, dose selection for cytotoxic chemotherapeutics has focused on the maximum tolerated dose, a paradigm that is less relevant for targeted therapies and new treatment modalities. A survey conducted by this group gathered insights from member companies regarding industry practices in oncology dose optimization. Given oncology drug development is a complex effort with multidimensional optimization and high failure rates due to lack of clinically relevant efficacy, this Working Group advocates for a case-by-case approach to inform the timing, specific quantitative targets, and strategies for dose optimization, depending on factors such as disease characteristics, patient population, mechanism of action, including associated resistance mechanisms, and therapeutic index. This white paper highlights the evolving nature of oncology dose optimization, the impact of Project Optimus, and the need for a tailored and evidence-based approach to optimize oncology drug dosing regimens effectively., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)