Acceptable Tolerability Research Articles

P0506 AZD7798, a monoclonal antibody depleting CCR9+ T cells, with the potential to target hard-to-treat small bowel Crohn’s disease

Abstract Background Crohn’s disease (CD) can affect any part of the gastrointestinal tract, but about 30% of patients have inflammation restricted to the ileum. In clinical trials, patients are typically enrolled irrespective of the disease localisation, with clinical outcomes focusing on a broad patient population. Anecdotally, small bowel healing in CD is often reported as challenging. Our aims were to investigate the unmet need in treating ileal CD and explore potential drug targets for this patient subpopulation. Methods A systematic review and meta-analysis was conducted of efficacy by disease location (Montreal classification L1 + L2) in placebo-controlled clinical trials in CD. As this revealed markedly different outcomes in ileal compared to colonic CD, transcriptomic data from 1185 small and large intestine biopsies of 594 CD patients were explored to identify potential small bowel specific drug targets, from which the chemokine receptor CCR9 emerged as high interest. AZD7798, a monoclonal antibody designed to deplete CCR9+ T cells, was evaluated in a randomized, placebo-controlled, double-blind first-in-human healthy volunteer study (NCT05452304), and in small bowel Crohn’s patients in a PET imaging study (NCT06053424). Results In the meta-analysis, marked differences were observed in efficacy of existing CD treatments in small compared to large bowel disease (Fig.1). Outcomes across mechanisms of action were not significantly different from placebo in small bowel CD (OR 1. 07, 95% CI 0.64-1.78, p=0.79) yet were superior in colonic CD (OR 3.86, 95% CI 2.75-5.42, p<0.001). Next, transcriptomic analyses identified CCR9 and its ligand CCL25 as highly and selectively expressed in terminal ileum compared to large bowel. Subsequently AZD7798, a CCR9+ T cell depleting antibody, was evaluated in 106 healthy participants in a first-in-human study, and in 6 CD patients in a Phase 1b study. There were no SAEs or treatment discontinuations, and rapid and sustained depletion of CCR9+ T cells in blood was observed in both studies. Moreover, AZD7798 reduced target cells in small bowel in CD patients as detected using a novel CCR9 tracer (Fig.2). Conclusion Ileal CD represents a high unmet need patient subpopulation, where existing treatments appear less effective than for colonic disease. CCR9 is identified as an attractive target for small bowel-dominant inflammation. AZD7798, a first-in-class CCR9+ T cell depleting antibody, demonstrated acceptable safety and tolerability alongside sustained CCR9+ T cell reductions in blood and small intestine.

P0874 Efficacy and tolerability of anti-tumor necrosis factor alpha therapy in refractory intestinal Behçet’s disease

Abstract Background Intestinal Behçet’s disease (BD) is a rare chronic intestinal vasculitic disorder and it is often refractory to conventional therapies such as corticosteroids and immunomodulators. We aimed to assess the efficacy and tolerability of anti-tumor necrosis factor alpha (TNF ɑ) in patients with moderate to severe intestinal BD who refractory to conventional therapy. Methods We analyzed patients with intestinal BD treated with anti-TNF ɑ more than 4 months registered at the Inflammatory Bowel Disease Clinic of Severance Hospital, Seoul, Korea. Clinical remission rates, clinical response rates, biological response rates at 4, 12, 24 months, and adverse events of anti-TNF ɑ treatment were investigated. We also examined relapse rates and predictive factors of relapse based on the BD-related surgery and admission. Results A total of 119 patients with intestinal BD were selected for the anti-TNF ɑ therapy, 15 (12.6%) were bio-exposed patients, 68 (57.1%) received concomitant immunomodulatory therapy, and 56 (47.1%) received concomitant corticosteroids at anti- TNF ɑ induction. At 4, 12, and 24 months after anti-TNF ɑ therapy, clinical remission rates were 23.5%, 40.3%, and 42%; clinical response rates were 84.0%, 62.2%, and 62.2%; and biological response rates were 61.3%, 68.9%, and 58.8%, respectively. Sixty-three (52.9%) patients presented disease relapse during follow-up period. The mean time before relapse was 2.8 years (median, 1.8 years). Higher initial CRP (hazards ratio [HR]: 1.013, 95% CI: 1.008-1.018, p < 0.001), previous surgery (HR: 4.282, 95% CI: 2.379-7.709, p < 0.001), concomitant immunomodulator (HR: 0.455, 95% CI: 0.27-0.775, p = 0.004), and clinical response at 4 months (HR: 0.353, 95% CI: 0.181-0.687, p = 0.002) were independent factors associated with the disease relapse in multivariate Cox regression analysis. There was no mortality in using anti-TNF ɑ agent. Twenty-six (21.8%) patients experienced infection, and 3 (2.5%) patients experienced infusion reaction. Conclusion Anti-TNF ɑ therapy could be a useful therapeutic option for refractory intestinal BD with an acceptable efficacy and tolerability profiles.

Metabolic Dysfunction-Associated Steatotic Liver Disease and the Cardiovascular System.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed nonalcoholic fatty-liver disease, is an important and rising health issue with a link with atherosclerotic cardiovascular (CV) disease (CVD), affecting ∼25-30% of the adults in the general population; in patients with diabetes, its prevalence culminates to ∼70%; its evolutive form, nonalcoholic steatohepatitis, is estimated to be the main cause of liver transplantation in the future. MASLD is a multisystem disease that affects, besides the liver, extra-hepatic organs and regulatory pathways; it raises the risk of type 2 diabetes mellitus (T2D), CVD, and chronic kidney disease; the disease may also progress to hepatocellular carcinoma. Its diagnosis requires hepatic steatosis and at least one cardiometabolic risk factor and the exclusion of both significant alcohol consumption and other competing causes of chronic liver disease. Beyond CV events, associated metabolic comorbidities comprise obesity (∼50%), T2D (∼20%), hyperlipidemia (∼70%), hypertension (∼40%), and metabolic syndrome (∼40%). Among the various clinical events, CV events mostly determine prognosis as they are the leading cause of death in these patients. Regarding management, statins exert beneficial effects in improving liver injury; silybin, derived from Silybum marianum, has some protective effects; lifestyle modification, such as weight loss, dietary changes, physical exercise, and abstention from alcohol use combined with optimal management of comorbidities are most helpful. Bariatric surgery may be an option in persons with MASLD and obesity. Adults with non-cirrhotic MASLD and significant liver fibrosis may be candidates for targeted treatment with resmetirom, which has histological efficacy on steatohepatitis and fibrosis with an acceptable safety and tolerability profile, whereas, no MASLD-targeted pharmacotherapy can be beneficial in the cirrhotic stage, whereby other measures may include metabolic drugs, nutritional counseling, surveillance for portal hypertension and hepatocellular carcinoma, and finally, liver transplantation in decompensated cirrhosis.

Safety, Tolerability, and Pharmacokinetics of a Novel Anti-obesity Agent, S-309309, in Healthy Adults with or Without Obesity.

Anti-obesity medications are recommended for patients who do not achieve and maintain weight loss despite lifestyle interventions. S-309309 is a novel oral inhibitor of monoacylglycerol O-acyltransferase 2 being developed as a treatment for obesity. The objective of the study was to investigate the safety, clinical pharmacology, pharmacokinetics and pharmacodynamic biomarker of S-309309. A phase I, single-center, two-part, randomized, double-blind, placebo-controlled study of S-309309 following oral administration of a single-ascending dose (part 1) and a multiple dose (part 2) in healthy adults with or without obesity was conducted. We also assessed the effect of food on the pharmacokinetics of S-309309 and the effect of S-309309 on electrocardiogram parameters, the pharmacokinetics of midazolam (a cytochrome P450 3A substrate), and the pharmacodynamic biomarker of monoacylglycerol O-acyltransferase 2 inhibition. In part 1 (N = 50), a single-ascending dose of S-309309 in healthy adults demonstrated dose proportionality and comparable exposure of S-309309 between the fasted and fed states. In part 2 (N = 24), no clinically meaningful difference was observed in the pharmacokinetics of multiple doses between healthy adults with or without obesity. S-309309 did not affect the pharmacokinetics of the cytochrome P450 3A substrate. The pharmacodynamic biomarker of monoacylglycerol O-acyltransferase 2 inhibition, dicarboxylic acid (18:1), was significantly increased after S-309309 administration in healthy adults with or without obesity. Overall, S-309309 demonstrated acceptable safety and tolerability without any serious adverse events or discontinuations because of adverse events, and did not have a clinically relevant effect on the heart rate or cardiac conduction. An effect on the placebo-corrected change-from-baseline corrected QT interval, corrected for heart rate using the Fridericia method, exceeding 10 ms can be excluded. S-309309 was well tolerated as single-dose (up to 300 mg) and multiple-dose (50 mg once daily for 14 days) oral administration. The pharmacokinetic characteristics remained unaffected by obesity and food intake. S-309309 did not affect the pharmacokinetics of the cytochrome P450 3A substrate. Overall, S-309309 had an acceptable safety profile and favorable pharmacokinetic and pharmacodynamic characteristics. NCT05247970, date of registration: 8 February, 2022.

A retrospective multicenter study on the efficacy and safety of disitamab vedotin monotherapy versus combination with anti-PD-1 immunotherapy in advanced gastric cancer

Novel therapeutic agents including disitamab vedotin (RC48, an antibody-drug conjugate) and immune-checkpoint inhibitors (e.g., PD-1 inhibitors) have provided new hope as an advanced gastric-cancer (GC) treatment. This multicenter retrospective study studied RC48 monotherapy (MT)’s efficacy and safety against its combination with anti-PD-1 immunotherapy (IT) in advanced GC. Patients treated with RC48 MT or RC48 combined with anti-PD-1 IT from July 2021 to April 2023 were recruited for the study. The progression-free survival (PFS), overall survival (OS), objective-response rate (ORR), disease-control rate (DCR), and safety were studied. After propensity score matching (PSM) (1:1), this study included 34 in the RC48 plus anti-PD-1 IT group and 34 in the RC48 MT group. The median PFS was significantly longer in the combination-therapy (CT) group than in the MT group (5.3 versus 3.8 months, HR: 0.51, 95% CI: 0.31–0.85, p = 0.010), and the median OS was also notably increased (10.0 versus 6.8 months, HR: 0.45, 95% CI: 0.27–0.77, p = 0.003). The ORR and DCR were higher in the combination group (41.18% versus 14.71%, p = 0.031; 61.76% versus 35.30%, p = 0.052). Moreover, subgroup analyses further revealed that those in the CT group experienced a longer PFS and OS, particularly those with high HER2 expression or a PD-L1 CPS score of 1 or higher. The combination therapy (CT) achieved acceptable tolerability and manageable adverse events. Furthermore, the most common grade 3–5 treatment-related adverse events (TRAEs) included decreased white-blood-cell (WBC) count, decreased neutrophil count, and anemia. No new safety risks were observed. In sum, the RC48 and anti-PD-1 IT combination showed good efficacy and a manageable safety profile, indicating its strong potential as an advanced GC therapeutic option.

Evaluation of the safety and efficacy of isotretinoin in treatment of COVID-19 : A randomized controlled clinical trial.

The pandemic of SARS-CoV2 is not only limited to the health issues and fatalities encountered in a worldwide overwhelming burden but also the social, economic, and well-being devastation. Many trials were done to find a safe and reliable therapy for COVID-19. Isotretinoin was reported as a possible therapy for COVID-19 through the mining of post-transcriptomic and genomic datasets, which revealed isotretinoin as a potent down-regulator of the ACE2 protein the crucial gateway of SARS-CoV2 to hijack host cells. A total of 106 patients with mild to moderate COVID-19 were recruited. Patients were randomized into two groups and treated with the Standard Care (STD) protocol of the Ministry of Health, Egypt, or the STD in combination with isotretinoin (0.5mg/kg/day) for 5days. The study involved 66 (63%) females and 39 (37%) males, median age 42years (interquartile 32-55.5 y). The main findings revealed a significant reduction in the time to improvement in the isotretinoin-treated (6.6±2 d) compared to the STD-treated patients (10.4±3.3). Survival analysis (HR: 4.1, 95% CI: 2.5-6.6) in comparison to the STD-treated patients. The main adverse event reported during the therapeutic duration was the dryness of the skin, which was of acceptable tolerability through skin care instructions to the patients. The data presented herein highlights the efficacy of isotretinoin in the management of mild to moderate COVID-19 patients with a significant reduction of the time to recovery. The adverse events reported were tolerable and did not outweigh the therapeutic benefits.

Analytical solutions for the stability analysis of coupled shear walls: Three-field CTB beam

To date, no closed-form analytical solutions have been proposed for calculating the global critical buckling load of symmetric and asymmetric coupled shear walls using a novel Three-field CTB continuous model. In this model, the coupled shear wall is represented as a three-field continuous system, formed by the parallel coupling of a Timoshenko beam with axial extensibility (representing the two shear walls) and a pure shear beam (representing the coupling beams), connected by rigid links. This continuous model, developed using a displacement-based approach and energy equivalence, effectively captures the three typical behaviors of a coupled shear wall: global bending, global shear, and local bending. Additionally, it accounts for a recently identified behavior arising from the local shear deformation of the walls, which has been largely overlooked in existing literature. Due to the complexity of its equilibrium equations, characterized by strong couplings among the three kinematic variables, solutions have been limited to static and dynamic analyses, restricting its application to stability analysis. To address this limitation, this study proposes, for the first time, three analytical solutions for the stability analysis of coupled shear walls subjected to arbitrary vertical loads. The first solution is an approximate yet accurate method that decouples the original model into two independent subsystems. The second provides an exact solution to the differential equation, while the third introduces an additional reduction factor to the exact solution. These proposed solutions offer varying levels of accuracy, all within acceptable engineering tolerances, enabling engineers and researchers to choose the appropriate method based on the required precision.

Disease activity and glucocorticoid tapering patterns in Japanese patients with systemic lupus erythematosus treated with anifrolumab: post hoc analysis of the Japanese subpopulation of the TULIP-2 study.

To investigate the efficacy of anifrolumab on disease activity and glucocorticoid tapering patterns in Japanese patients with systemic lupus erythematosus (SLE). We analysed disease activity and glucocorticoid tapering in the Japanese subpopulation (anifrolumab, n = 24; placebo, n = 19) of the TULIP-2 trial, which showed the efficacy and safety of anifrolumab in patients with moderate-to-severe active SLE. The percentage of patients who achieved a British Isles Lupus Assessment Group-based Composite Lupus Assessment response at Week 52 was greater in the anifrolumab group than placebo [50.0% (12/24) vs. 15.8% (3/19); p = 0.014]. Lupus low disease activity state (LLDAS) was achieved at Week 52 by 9/24 (37.5%) and 3/19 (15.8%) patients receiving anifrolumab and placebo, respectively. During the 52-week study period, in the anifrolumab vs. placebo groups, 5/24 (20.8%) patients were in LLDAS ≥50% of observed time vs. 0/19 (0.0%), and 14/24 (58.3%) vs. 6/19 (31.6%) patients were classified into favourable glucocorticoids tapering pattern. Anifrolumab had an acceptable tolerability profile, consistent with the overall population. In the Japanese subpopulation of the TULIP-2 trial, anifrolumab resulted in an improvements in disease activity to those reported for the overall population, suggesting a beneficial effect for disease control.

Repurposing Licensed Drugs with Activity Against Epstein-Barr Virus for Treatment of Multiple Sclerosis: A Systematic Approach.

Epstein-Barr virus (EBV) is implicated as a necessary factor in the development of multiple sclerosis (MS) and may also be a driver of disease activity. Although it is not clear whether ongoing viral replication is the driver for MS pathology, MS researchers have considered the prospect of using drugs with potential efficacy against EBV in the treatment of MS. We have undertaken scientific and lived experience expert panel reviews to shortlist existing licensed therapies that could be used in later-stage clinical trials in MS. A list of therapies with anti-EBV effects was developed from existing reviews. A detailed review of pre-clinical and clinical data was undertaken to assess these candidates for potential usefulness and possible harm in MS. A 'drug-CV' and a plain language version focusing on tolerability aspects was created for each candidate. We used validated criteria to score each candidate with an international scientific panel and people living with MS. A preliminary list of 11 drug candidates was generated. Following review by the scientific and lived experience expert panels, six yielded the same highest score. A further review by the expert panel shortlisted four drugs (famciclovir, tenofovir alafenamide, maribavir and spironolactone) deemed to have the best balance of efficacy, safety and tolerability for use in MS. Scientific and lived experience expert panel review of anti-EBV therapies selected four candidates with evidence for efficacy against EBV and acceptable safety and tolerability for potential use in phase III clinical trials for MS.

AZD2693, a PNPLA3 antisense oligonucleotide, for the treatment of MASH in 148M homozygous participants: two randomized phase I trials.

A common genetic variant (rs738409) encoding isoleucine to methionine at position 148 in the PNPLA3 protein is a determinant of hepatic steatosis, inflammation, fibrosis, cirrhosis, and liver-related mortality. AZD2693 is a liver-targeted antisense oligonucleotide against PNPLA3 mRNA. We evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics in single ascending dose (SAD) and multiple ascending dose (MAD) studies. AZD2693 was assessed in 3D cultures of homozygous PNPLA3 148M primary human hepatocytes and mice expressing human PNPLA3. The SAD study investigated 2-110 mg doses in overweight/mildly obese but otherwise healthy volunteers. The MAD study investigated three monthly doses (25 mg, 50 mg and 80 mg) in participants with magnetic resonance imaging proton density fat fraction (MRI-PDFF) ≥ 7%. Changes in liver fat content were assessed at baseline, weeks 8 and 12 by MRI-PDFF. PNPLA3 mRNA and protein knockdown levels were evaluated for the 80 mg dose. AZD2693 potently reduced PNPLA3 expression in human hepatocytes and livers of mice. Clinically, AZD2693 was generally well tolerated (no adverse events leading to discontinuation or treatment related serious adverse events). Half-life was 14-33 days across investigated doses. A least-square (LS) mean liver PNPLA3 mRNA knockdown of 89% and reduction of protein levels demonstrated target engagement. Changes in hepatic steatosis at week 12 were -7.6% and -12.2% (placebo-corrected LS means) for the 25 mg and 50 mg doses, respectively. There was a dose-dependent increase of polyunsaturated fatty acids in serum triglycerides and decreases vs placebo in high-sensitivity C-reactive protein and interleukin 6. AZD2693 reduced liver PNPLA3 with an acceptable safety and tolerability profile. These findings support the continued development of AZD2693. NCT04142424, NCT04483947 IMPACT AND IMPLICATIONS: Clinical treatment options for MASH are limited. The genetic risk factor with the largest effect size for progressing to poor liver-related outcomes in MASH is a single-nucleotide polymorphism in the gene PNPLA3 (p.I148M). In Phase 1 SAD and MAD studies, AZD2693, a liver-targeted antisense oligonucleotide was well tolerated, reduced liver PNPLA3 mRNA and protein levels, and dose dependently reduced liver fat content in homozygous PNPLA3 148M risk allele carriers. These data support continued development of AZD2693 as a potential precision medicine treatment for MASH. The Phase 2b FORTUNA study is now ongoing.

FINANCIAL FRAUD DETECTION USING VALUE AT RISK WITH MACHINE LEARNING IN SKEWED DATA

The significant losses that banks and other financial organizations suffered due to new bank account (NBA) fraud are alarming as the number of online banking service users increases. The inherent skewness and rarity of NBA fraud instances have been a major challenge to the machine learning (ML) models and happen when non-fraud instances outweigh the fraud instances, which leads the ML models to overlook and erroneously consider fraud as non-fraud instances. Such errors can erode the confidence and trust of customers. Existing studies consider fraud patterns instead of potential losses of NBA fraud risk features while addressing the skewness of fraud datasets. The detection of NBA fraud is proposed in this research within the context of value-at-risk as a risk measure that considers fraud instances as a worst-case scenario. Value-at-risk uses historical simulation to estimate potential losses of risk features and model them as a skewed tail distribution. The risk-return features obtained from value-at-risk were classified using ML on the bank account fraud (BAF) Dataset. The value-at-risk handles the fraud skewness using an adjustable threshold probability range to attach weight to the skewed NBA fraud instances. A novel detection rate (DT) metric that considers risk fraud features was used to measure the performance of the fraud detection model. An improved fraud detection model is achieved using a K-nearest neighbor with a true positive (TP) rate of 0.95 and a DT rate of 0.9406. Under an acceptable loss tolerance in the banking sector, value-at-risk presents an intelligent approach for establishing data-driven criteria for fraud risk management.

The Influence of the Age Factor on The Quest for Value for Money in The Phenomenon of Electronic Product Leveling

With the continuous development of electronic product technology, a large number of reasonably priced, high-performance flat products have appeared on the market. This phenomenon reflects that consumers are highly concerned about the price-performance ratio. The age factor plays an important role in consumers' purchasing decisions, and there are significant differences in the behaviors and preferences of consumers of different age groups in the pursuit of cost-effective products. In this paper, we conduct an in-depth analysis of the demand, purchasing behavior and preference of consumers of different age groups in the phenomenon of electronic product replacement, and explore how the age factor affects consumers' pursuit of cost-effectiveness. It is found that there are significant differences between teenagers, middle-aged people and the elderly in terms of their concern for cost-effectiveness, purchase decision-making process and brand preference. In the phenomenon of electronic product parity, young people are more concerned with appearance and trends, middle-aged people emphasize comprehensive value and rational comparison, and older people tend to choose brands that are easy to use and trustworthy. These differences are closely related to consumers' economic status, consumer attitudes, technology acceptance, and risk tolerance. This paper aims to provide a reference for marketing strategies in the electronics market and to provide new perspectives for future research.

Neoadjuvant Immunotherapy and De-escalation of Surgery in Locally Advanced Breast Implant-associated Anaplastic Large Cell Lymphoma.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare form of non-Hodgkin T-cell lymphoma diagnosed in patients with a history of breast implants. Most patients develop a periprosthetic effusion at early stages of disease while less common presentations include a palpable mass, severe capsular contracture, lymphadenopathy, or cutaneous erythema. Due to the complex nature of this disease, a multidisciplinary approach is necessary for optimal management, particularly in locally advanced disease or inoperable patients. We present the successful use of neoadjuvant therapeutic protocols in two cases of locally advanced BIA-ALCL. The first case was a 52-year-old patient with a left breast mass-like stage III disease who underwent combined targeted immunotherapy and chemotherapy (brentuximab vedotin [BV]-cyclophosphamide, doxorubicin, prednisone [CHP]). Following a complete radiological and metabolic response, the patient underwent bilateral implant removal, right total intact capsulectomy, left en bloc capsulectomy, and skin resection from the left inframammary fold in continuity with the capsule. The second case was a 65-year-old patient with right breast swelling and mass-like stage IIA disease who received targeted immunotherapy, BV. Following a complete metabolic response, she underwent bilateral implant removal and en bloc capsulectomy. A literature review and the reported cases suggest the effectiveness of targeted immunotherapy as monotherapy or in combination with chemotherapy in locally advanced BIA-ALCL in disease downstaging, surgical de-escalation, reduction of significant postoperative complications, and an acceptable tolerance profile. Although surgery is an essential part of treatment, the timing and type of intervention should be carefully planned, especially when primary, radical resection is uncertain.

Population Pharmacokinetics of Trofinetide in a Pediatric Population Aged 2-4Years with Rett Syndrome.

Weight-banded trofinetide dosing improved physician- and caregiver-rated efficacy measures and had acceptable tolerability in patients aged 2‒4years (DAFFODIL study) and 5‒20years (LAVENDER study) with Rett syndrome (RTT). Selection of weight-banded dosing regimens for these studies was based on population pharmacokinetic (popPK) modeling and exposure simulations. This study applied an updated popPK model to confirm steady-state trofinetide exposures achieved in DAFFODIL patients were within target range. A popPK model was developed using data from 14 clinical studies of trofinetide in healthy volunteers and pediatric and adult patients, including the LAVENDER and DAFFODIL studies. Individual exposure measures (area under concentration-time curve over 0-12h [AUC0-12] were generated via integration of the predicted concentration-time profile for each DAFFODIL study participant based on the popPK model and individual empiric Bayesian pharmacokinetic parameter estimates. Distributions of steady-state AUC0-12 values for each body-weight group were compared against target exposure (AUC0-12 = 800‒1200µg·h/mL). Distribution and box plots of simulated steady-state AUC0-12 values achieved with the weight-banded DAFFODIL dosing regimen used in younger individuals aged 2-4years with RTT (twice daily trofinetide 5g[≥ 9 to < 12kg] or 6g [≥ 12 to < 20kg]) indicated good overlap with the target exposure range. Median steady-state AUC0-12 values for both body-weight bands fell within the target exposure range. PopPK model-based simulations confirm that the weight-banded dosing regimen used in DAFFODIL is adequate to achieve target trofinetide exposure in 2- to 4-year-olds with RTT.

First-in-Human Study of 23ME-00610, an Antagonistic Antibody for Genetically Validated CD200R1 Immune Checkpoint, in Participants with Advanced Solid Malignancies.

In this phase 1 portion of a first-in-human phase 1/2a study (NCT05199272), 23ME-00610 was evaluated in participants with advanced solid malignancies to determine its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD). Exploratory biomarkers were evaluated to examine potential correlates of efficacy and safety. Eligible participants (≥18 years) were administered 23ME-00610 intravenously every 3 weeks (Q3W) using an accelerated titration design followed by a traditional 3 + 3 design, with an initial dose level of 2 mg. Twenty-eight participants were enrolled across seven cohorts and received a median of four cycles of 23ME-00610. No treatment-related serious adverse events (AE) were observed, and the maximum tolerated dose was not reached. Overall, the PK of 23ME-00610 was linear and dose proportional for doses ≥60 mg, with a median terminal half-life of 13 days at 1,400 mg. Peripheral saturation of CD200R1 was observed for doses ≥60 mg. Immune-related AEs, including rash, pruritus, and hypothyroidism, were predicted by phenome-wide association studies and observed for doses ≥60 mg. A confirmed partial response was observed in a participant with well-differentiated pancreatic neuroendocrine cancer whose tumor was among those with the highest tumor CD200 expression. 23ME-00610 has mild-to-moderate on-target AEs and PK/PD consistent with tumor target saturation and dosing every 3 weeks. The trend for clinical benefit in participants with tumor CD200 expression suggests that 23ME-00610 inhibits CD200R1 signaling and may reverse CD200-mediated immune evasion. Based on PK/PD, safety, and preliminary antitumor activity, 1,400 mg Q3W was selected as the dose for further study. Genome-wide association studies (GWAS) of the 23andMe genetic database identified CD200R1 as a promising therapeutic target for cancer. This phase 1 study of 23ME-00610, a CD200R1 antagonist IgG1, showed acceptable safety and tolerability, PK supporting Q3W dosing, and PD and preliminary clinical activity supporting an initial recommended phase 2 dose of 1,400 mg.

E-52862-A selective sigma-1 receptor antagonist, in peripheral neuropathic pain: Two randomized, double-blind, phase 2 studies in patients with chronic postsurgical pain and painful diabetic neuropathy.

We report the efficacy and safety of E-52862-a selective, sigma-1 receptor antagonist-from phase 2, randomized, proof-of-concept studies in patients with moderate-to-severe, neuropathic, chronic postsurgical pain (CPSP) and painful diabetic neuropathy (PDN). Adult patients (CPSP [N = 116]; PDN [N = 163]) were randomized at a 1:1 ratio to 4 weeks of treatment with E-52862 (CPSP [n = 55]; PDN [n = 85]) or placebo (CPSP [n = 61]; PDN [n = 78]) orally once daily. Pain intensity scores were measured using a numerical pain rating scale from 0 (no pain) to 10 (worst pain imaginable). The primary analysis population comprised patients who received study drug with ≥1 baseline and on-treatment observation (full analysis set). In CPSP, mean baseline average pain was 6.2 for E-52862 vs. 6.5 for placebo. Week 4 mean change from baseline (CFB) for average pain was -1.6 for E-52862 vs. -0.9 for placebo (least squares mean difference [LSMD]: -0.9; p = 0.029). In PDN, mean baseline average pain was 5.3 for E-52862 vs. 5.4 for placebo. Week 4 mean CFB for average pain was -2.2 for E-52862 vs. -2.1 for placebo (LSMD: -0.1; p = 0.766). Treatment-emergent adverse events (TEAEs) were reported in 90.9% of E-52862-treated patients vs. 76.7% of placebo-treated patients in CPSP and 34.1% vs. 26.9% in PDN. Serious TEAEs occurred in CPSP only: E-52862: 5.5%; placebo: 6.7%. E-52862 demonstrated superior relief of CPSP vs. placebo after 4 weeks. Reductions in pain intensity were seen in PDN with E-52862; high placebo response rates may have prevented differentiation between treatments. E-52862 had acceptable tolerability in both populations. These proof-of-concept studies validate the mode of action of E-52862, a selective sigma-1 receptor antagonist. In CPSP, E-52862 resulted in clinically meaningful pain relief. In PDN, reductions in pain intensity were seen with E-52862; high placebo response rates may have prevented differentiation between E-52862 and placebo. These findings are clinically relevant given that neuropathic pain is highly incapacitating, lacking effective treatments and representing a significant unmet medical need, and support further development of sigma-1 receptor antagonists for peripheral neuropathic pain.

Five‐year evaluation of linear accelerator‐based SRS platform isocentricity

AbstractLinear accelerator (LINAC)‐based stereotactic radiosurgery (SRS) has become a mainstay in the management of intracranial tumors. However, the high fractional doses and sharp gradients used in SRS place heavy demands on geometric accuracy. Image guidance systems such as ExacTrac (ETX, Brainlab AG, Munich, Germany) have been developed to facilitate position verification at nonzero table angles. Though convenient, potential loss of mechanical rigidity between the imaging and treatment systems can be cause for concern, as the ETX system is not mounted to the rotating gantry. In this retrospective study, we analyzed 518 Winston‐Lutz (WL) tests performed in the last 5 years with ETX alignment on our Elekta Versa HD (Elekta AB, Stockholm, Sweden) linear accelerator to determine the achievable limits of precision and stability over time for our LINAC‐based SRS platform. Results demonstrated remarkable stability over time. 3D and directional misalignments never exceeded 1.0 mm over the study period; however, table rotation was shown to be the most significant source of positional uncertainty. Gantry sag, as measured by gun‐to‐target misalignments at the gantry‐0 and gantry‐180‐degree positions, was consistent, measuring 1.23 ± 0.18 mm over the study period. Measured accuracy was well within acceptable tolerances for cranial SRS treatment delivery. Notably, the use of the ETX system for intrafraction repositioning effectively eliminates couch walkout, the most significant source of uncertainty identified in this study. Our results thus corroborate safe SRS treatment delivery on our Versa HD with ExacTrac image guidance.

Discovery and development of INNA-051, a TLR2/6 agonist for the prevention of complications resulting from viral respiratory infections.

Viral respiratory infection is associated with significant morbidity and mortality. The diversity of viruses implicated, coupled with their propensity for mutation, ignited an interest in host-directed antiviral therapies effective across a wide range of viral variants. Toll-like receptors (TLRs) are potential targets for the development of broad-spectrum antivirals given their central role in host immune defenses. Synthetic agonists of TLRs have been shown to boost protective innate immune responses against respiratory viruses. However, clinical success was hindered by short duration of benefit and/or induction of systemic adverse effects. INNA-051, a TLR2/6 agonist, is in development as an intranasal innate immune enhancer for prophylactic treatment in individuals at risk of complications resulting from respiratory viral infections. In vivo animal demonstrated the efficacy as prophylaxis against multiple viruses including SARS-CoV-2, influenza, and rhinovirus. Early clinical trials demonstrated an acceptable safety and tolerability profile. Intranasal delivery to the primary site of infection in humans induced a local innate host defense response characterized by innate immune cell infiltration into the nasal epithelium and activation and antiviral response genes . Taken together, the preclinical and clinical data on INNA-051 support further investigation of its use in community infection setting.

Safety, tolerability, pharmacokinetics, and antimalarial activity of MMV533: a phase 1a first-in-human, randomised, ascending dose and food effect study, and a phase 1b Plasmodium falciparum volunteer infection study.

Novel antimalarials are needed to address emerging resistance to artemisinin and partner drugs. We did two trials to evaluate safety, tolerability, pharmacokinetics, and activity against blood stage Plasmodium falciparum for the drug candidate MMV533. A phase 1a first-in-human (FIH) trial was conducted at Nucleus Network (Melbourne, VIC, Australia). Part 1 was a double-blind, randomised, placebo-controlled, sequential ascending dose study and part 2 was an open-label, randomised, two-period crossover, pilot food effect study. A phase 1b, open-label, volunteer infection study (VIS) was conducted at Nucleus Network (Herston, QLD, Australia). Eligible participants were adults aged 18-55 years, with a bodyweight of at least 50 kg and BMI of 18-32 kg/m2 and participants in the VIS were malaria-naive. In part 1 of the FIH study, six cohorts of up to eight participants were randomly assigned (3:1) to a single oral MMV533 dose (5, 10, 20, 50, 100, and 160 mg) or placebo using an automated system, with study staff and participants masked to treatment allocation, and follow-up until day 28. In part 2, MMV533 30 mg was administered open-label to one cohort of nine participants assigned by simple randomisation (1:1) to the fasted-fed (n=4) or fed-fasted (n=5) groups. After a 21-day washout period, fed and fasted groups crossed over with follow-up until day 42. In the VIS, seven participants were assigned using simple randomisation (1:1:1) to three dosing groups of 20 mg (n=3), 35 mg (n=2), or 100 mg (n=2) after parasitaemia was detected, with follow-up until day 28. The primary outcomes were treatment emergent adverse events and relationship to MMV533 for the FIH study assessed in the safety population, and in the VIS primary outcomes were parasite reduction ratio over 48 h (log10PRR48), parasite clearance half-life (PCT1/2), and lag phase assessed in the pharmacodynamic population. MMV533 pharmacokinetics was a secondary outcome for both studies, evaluated in the pharmacokinetic population. The studies are registered with ClinicalTrials.gov, NCT04323306 and NCT05205941 (completed). The FIH study was conducted between July 31, 2020, and Sept 27, 2022, and the VIS between March 31 and Aug 9, 2022. 335 adults were assessed for eligibility, 71 enrolled, and 69 randomly assigned (53 in part 1 and nine in part 2 of the FIH study, and seven in the VIS). 32 (45%) of 71 participants were female and 39 (55%) were male. In part 1, 24 (63%) of 38 participants had an adverse event after MMV533 administration with no apparent relationship to dose versus six (50%) of 12 after placebo. Treatment-related adverse events were reported for four (11%) participants receiving MMV533 and one (8%) receiving placebo, with no relationship to dose. In part 2, adverse events were reported for three (38%) of eight participants when fasted and four (44%) of nine when fed, with no apparent influence of food. Time to maximum plasma concentration was 4·0-6·0 h, and apparent half-life was 103·8-127·2 h. After a high-fat meal, the geometric mean ratio (fed:fasted) of MMV533 AUC0-last was 112·0 (90% CI 89·6-140·0). In the VIS for MMV533 100 mg, log10PRR48 was 2·27 (1·99-2·56), PCT1/2 was 6·36 h (5·64-7·28), and lag phase was 2 h. An acceptable safety and tolerability profile, confirmed parasiticidal activity, and a long half-life support progression of MMV533 into clinical trials in patients with malaria as a component of new antimalarial combination therapies. MMV Medicines for Malaria Venture and Bill & Melinda Gates Foundation.

An insight into the use of extruded brewers’ spent grain as a healthy human snack ingredient. Effects on food structure, sensory quality, satiety and gastrointestinal tolerance

Reduced in sugar biscuits made with fructooligosaccharides (15.2%) and 0%, 8% and 17% of extruded brewers' spent grain (EBSG) were formulated as a healthy snack. The investigation aimed to study the impact of the formulation on technological parameters, sensory attributes and gastrointestinal effects. Biscuits’ hardness, color, water and oil holding capacity, starch gelatinization and microstructure were analyzed. Products were tested in a randomized blind cross-over design trial with 51 adults, determining sensory acceptance, satiety and gastrointestinal tolerance. Results showed an addition of 17% EBSG caused product hardening, darker color, and a more compact structure. These parameters were in line with consumers' product description and caused lower acceptability, while the acceptability of biscuits with 8% or 0% EBSG did not differ (p > 0.05). However, biscuits with 17% of EBSG were the only ones to exhibit a positive effect on short-term appetite control. Formulations showed good and similar gastrointestinal tolerance (p > 0.05).