Dose-ranging Study Research Articles

The biochemical effects of kola nitida on the renal biomarkers of lipid induced Wistar albino rats

The aim of the study was to access the biochemical effects of kola nitida extract on renal markers of adult albino rats induced with high lipid diet. This was a prospective longitudinal study carried out in Joseph Ayo Babalola University, Ikeji Arakeji, Osun State Students. The study was conducted within a period of 6 months (April– September 2024). The study adhered to stringent animal husbandry protocols. Rats were housed individually in standard laboratory cages with controlled environmental conditions (temperature 22±2°C, humidity 50-60%, and a 12-hour light/dark cycle) to minimize environmental variability. They had unrestricted access to standard rodent feed and water throughout the experiment to maintain optimal health and consistent metabolic conditions. The experimental design involved the administration of kola nitida extract via oral gavage at predetermined doses based on body weight, established through preliminary dose-ranging studies to ensure safety and efficacy. Animals were randomly assigned to experimental and control groups, with each group carefully monitored for behavioral changes and physical health indicators throughout the study period. Grouping of animals was done as the animals were divided into 5 groups: Group 1(Negative control), Group 2(Toxicity group), Group 3(100mg/kg), Group 4(200 mg/kg), Group 5(300mg/kg). Blood samples was collected from the marginal ear vein using a 2ml needle and syringe into lithium heparin bottles and was spun at 3500 rpm for 5 minutes to obtain plasma in order to determine the renal biomarkers using creatinine and urea diagnostic kit (Randox test kit), The results of this study clearly demonstrate that the administration of a high lipid diet and subsequent reversal with Kola-Nitida induces significant changes in the urea and creatinine in all the test groups when compared to toxicity group. The strong statistical evidence supports the conclusion that Kola-Nitida may play a role in mitigating the effects of a high lipid diet on the renal biomarkers in Wistar rats.

Formulation development of dual-compartment topical inserts combining Tenofovir Alafenamide and Elvitegravir for flexible on-demand HIV prevention

Pre-exposure prophylaxis (PrEP) has emerged as a prominent approach for the prevention of HIV infections. While the latest advances have resulted in effective oral and injectable product options, there are still gaps in on-demand, event-driven, topical products for HIV prevention that are safe and effective. Here we describe the formulation development of a dual-compartment topical insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) that may be administered when needed, vaginally or rectally, pre- or post-coitus, for flexible HIV prophylaxis. Specifically, we describe the lab-scale formulation development, preclinical mucosal safety and pharmacokinetics (PK) testing in rabbits, long-term stability, and scale-up clinical manufacturing of the lead TAF/EVG (20 mg/16 mg) inserts, which are currently in clinical stages of development. As designed, the inserts are small, discreet and portable, offering a number of promising attributes, such as simple and robust direct-compression manufacturing, fast initial disintegration/dissolution, and suitable mechanical strengths showing low hardness (<8 kg), friability (<1 %), and moisture content (<1 %). The inserts initiated disintegration quickly (~ ≤ 15 min) providing full in vitro release (>90 %) of TAF and EVG within 60 min of dissolution. The lead insert was selected from formulation prototypes that met the evaluation criteria for manufacturability and characterization, together with a dose-ranging PK study in non-human primates. Successful technology transfer for clinical development of the lead TAF/EVG (20 mg/16 mg) insert was confirmed under cGMP conditions. Based on the 12 months (lab-scale) and 24 months (clinical batch) stability data, the TAF/EVG inserts are projected to have a long shelf life of over 2 years, if stored at or below 30 °C/65 % RH. Overall, these newly designed topical inserts have formulation properties that enable stable storage and fast release of the antiretroviral payload from a small, portable and discreet dosage form. They are safe and effective when applied vaginally or rectally, before or after coitus, providing the basis for a new method of flexible on-demand HIV prevention for cisgender and transgender women and men. The TAF/EVG inserts are currently the most clinically advanced on-demand topical product, as attested by their completed and ongoing clinical trials.

Safety and Efficacy of Ianalumab in Patients With Sjögren's Disease: 52-Week Results From a Randomized, Placebo-Controlled, Phase 2b Dose-Ranging Study.

To report 52-week safety and efficacy of ianalumab from phase 2b dose-finding study in patients with Sjögren's disease (SjD). Patients randomly received (1:1:1:1) ianalumab (5, 50, or 300 mg) or placebo subcutaneously every 4 weeks till week 24 (treatment period [TP]1). At week 24, patients on 300 mg were re-randomized to continue 300 mg or receive placebo till week 52 (TP2), patients on placebo were switched to ianalumab 150 mg, while patients on 5 and 50 mg directly entered post treatment safety follow-up. Patients who discontinued treatment early or completed treatment entered safety follow-up (≥20 weeks). During TP1, 190 patients were randomized (placebo=49, 5 mg=47, 50 mg=47, 300 mg=47). Of these 190 patients, 90 (47.4 %; 43 continued 300 mg and 47 received placebo) entered TP2, and 81/90 (90.0%) completed the study treatment. By week 52, efficacy was sustained in patients who continued 300 mg in TP2 (ESSDAI, ESSPRI, PaGA, PhGA change from week 24: -1.45, -0.46, -4.69, -6.86, respectively). Stimulated salivary flow rates and autoantibody levels numerically improved in the 300 mg group. Treatment-emergent adverse events were not dose-dependent, except for injection-site reactions. Cases of decreased neutrophil counts (CTCAE v4.03 grade 3 according to laboratory listings) were observed in 3 patients during the post-treatment follow-up, occurring at 3.5, 5.5, and 3 months, after the last ianalumab administration. None were associated with infection except one incidental finding of asymptomatic cytomegalovirus infection (IgM+). In patients with SjD, ianalumab 300 mg demonstrated sustained efficacy through week 52 and a favorable safety profile up to two years of follow-up.

Abstract 4115645: NLRP3 Inflammasome Inhibition With Dapansutrile in Type 2 Diabetes and Elevated Systemic Inflammation: Rationale and Design of the DAPAN-DIA study

Background: Monoclonal antibodies against IL-1β decrease inflammation, improve insulin secretion and glycaemia, and reduce residual CV risk, but must be injected and are associated with higher incidence of fatal infection. There remains an unmet need for an oral treatment for T2D patients at risk for cardiometabolic complications to safely reduce IL-1β-mediated inflammation chronically&amp;with low risk of immunosuppression. In an initial dose-range finding study in heart failure patients with T2D, we reported evidence of anti-hyperglycaemic efficacy and improvement in LVEF with dapansutrile an oral specific inhibitor of the NLRP3 inflammasome. Objectives: To investigate the potential of preventing the transition to organ complications, The EU funded consortium INTERCEPT-T2D in collaboration with US based biotech Olatec Therapeutics has launched a clinical trial of anti-inflammatory therapy with dapansutrile targeting T2D patients with low-grade inflammation. Methods: Dapansutrile in Diabetes and Complications (DAPAN-DIA, NCT06047262) aims to determine whether NLRP3 inhibition with dapansutrile has the potential to not only improve glycaemia but also reduce micro- and macro-vascular risk and complications from diabetes. DAPAN-DIA is a multicenter, pbo-controlled, prospective, randomized, double-blind trial conducted in Switzerland, France, Belgium and Germany. A total of 300 patients with T2D, HbA1c &gt;7.5% and hsCRP&gt;1.5 mg/L are being randomized to either dapansutrile 1000 mg BID or matching PBO tablets for 6 months (2:1 ratio dapansutrile: pbo). The primary endpoint is change from baseline HbA1c. Secondary endpoints include biomarkers associated with diabetic complications, progression of MASLD as well as chronic inflammation (IL-1 β, IL-6 and hsCRP). A subject-assessed QoL questionnaire is also collected. To detect an absolute difference of 0.5% in HbA1c between groups, approximately 300 subjects will be randomized 2:1 ratio to achieve 80% power, assuming a standard deviation of 1.2% in change from baseline in HbA1c at week 26. Results: The trial has launched and currently is enrolling subjects. Conclusions: DAPAN-DIA is the first placebo-controlled, adequately powered, large, multi-center study with an oral NLRP3-specific Inhibitor, dapansutrile. The trial will generate important data on a new clinically relevant dimension in T2D care where consideration at diagnosis of inflammatory parameters are of importance for the transition to T2D-related complications.

FRONTIER-2: A phase 2b, long-term extension, dose-ranging study of oral JNJ-77242113 for the treatment of moderate-to-severe plaque psoriasis

BackgroundMore patients with moderate-to-severe plaque psoriasis achieved responses with JNJ-77242113, a targeted oral peptide inhibiting interleukin (IL)-23 receptor signaling, versus placebo at Week(W)16 of the phase 2 FRONTIER-1 study. ObjectiveFRONTIER-2, a long-term extension of FRONTIER-1, evaluated JNJ-77242113 through 1 year. MethodsFRONTIER-1 participants received JNJ-77242113 at doses from 25mg once daily (QD) to 100mg twice daily (BID) or placebo, through W16. Patients completing FRONTIER-1 could enroll in FRONTIER-2 and continue JNJ-77242113 at the same dose through W52. Those on placebo crossed over to JNJ-77242113 100mg QD for W16–52. Safety follow-up continued through W56. ResultsMost (89%) FRONTIER-1 patients continued to FRONTIER-2. Across outcomes, response rates were maintained from W16–52. The highest response rates generally occurred with JNJ-77242113 100mg BID. At W52, 76% of patients achieved up to 75% improvement in Psoriasis Area and Severity Index (PASI75) with 100mg BID; rates of clear or almost clear skin were 64% (PASI90), 74% (Investigator’s Global Assessment [IGA]0/1), 40% (PASI100), and 43% (IGA 0). From W16–56, 59% of JNJ-77242113–treated patients had ≥1 adverse events (AEs). Serious AEs, considered unrelated to treatment by investigators, occurred in 4% of patients. LimitationsThe study was limited by the small number of patients in each treatment group and the descriptive nature of the longer-term data. ConclusionRates of skin clearance with JNJ-77242113 were durable to 1 year and no safety signals were identified.

Evaluation of an oral small-molecule glucagon-like peptide-1 receptor agonist, lotiglipron, for type 2 diabetes and obesity: A dose-ranging, phase 2, randomized, placebo-controlled study.

The aim was to investigate the effects of lotiglipron, a once-daily, oral small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist, in participants with type 2 diabetes (T2D) or obesity. A phase 2, randomized, double-blind, placebo-controlled, dose-ranging study investigated the efficacy and safety of lotiglipron. The study was terminated early for safety reasons after routine data and monitoring review. The planned analyses for the end points were modified prior to unblinding the study. In total, 901 participants were treated with at least one dose of the study drug (T2D cohort: n = 512, obesity cohort: n = 389). Although the majority of participants who were randomly assigned to higher doses did not reach their target maintenance dose, statistically significant changes in HbA1c and body weight were observed. In the T2D cohort, reductions in HbA1c were observed across all lotiglipron doses at week 16 (p < 0.0001), with least squares mean decreases up to -1.44% (90% confidence interval [CI]: -1.63, -1.26) (lotiglipron 80 mg), versus placebo, -0.07% (90% CI: -0.25, 0.11). In the obesity cohort, decreases in body weight were observed across all lotiglipron doses at week 20 (p < 0.01), up to -7.47% (90% CI: -8.50, -6.43) (lotiglipron 200 mg, five-step titration), versus placebo, -1.84% (90% CI: -2.85, -0.83). Across cohorts, the most frequently reported treatment-emergent adverse events were gastrointestinal related (most mild to moderate severity), with nausea being the most common (ranging from 4% [placebo] to 28.8% [80 mg] in the T2D cohort and 12.5% [placebo] to 60.6% [200 mg, four-step titration] in the obesity cohort). Transaminase elevations were observed in a subset of participants (6.6% and 6.0% of participants on lotiglipron in the T2D and obesity cohorts, respectively, compared with 1.6% on placebo in the obesity cohort). The efficacy (HbA1c and/or body weight) of a range of lotiglipron doses was demonstrated in T2D and obesity cohorts. The safety profile was largely consistent with what has been previously known about the mechanism of action. Our results are unique in reporting elevations in liver transaminases in a subset of participants treated with lotiglipron, with attempts to identify the at-risk population unsuccessful and therefore clinical development of lotiglipron terminated. GOV: NCT05579977.

Understanding the mechanisms of food effect on omaveloxolone pharmacokinetics through physiologically based biopharmaceutics modeling.

Omaveloxolone is a nuclear factor (erythroid-derived 2)-like 2 activator approved in the United States and the European Union for the treatment of patients with Friedreich ataxia aged ≥16 years, with a recommended dosage of 150 mg orally once daily on an empty stomach. The effect of the US Food and Drug Administration (FDA) high-fat breakfast on the pharmacokinetic profile of omaveloxolone observed in study 408-C-1703 (NCT03664453) deviated from the usual linear correlation between fed/fasted maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) ratios reported for various oral drugs across 323 food effect studies. Here, physiologically based biopharmaceutics modeling (PBBM) was implemented to predict and explain the effect of the FDA high-fat breakfast on a 150-mg dose of omaveloxolone. The model was developed and validated based on dissolution and pharmacokinetic data available across dose-ranging, food effect, and drug-drug interaction clinical studies. PBBM predictions support clinical observations of the unique effect of a high-fat meal on omaveloxolone pharmacokinetic profile, in which the Cmax increased by 350% with only a 15% increase in the AUC. Key parameters influencing omaveloxolone pharmacokinetics in the fasted state based on a parameter sensitivity analysis included bile salt solubilization, CYP3A4 activity, drug substance particle size distribution, and permeability. Mechanistically, invivo omaveloxolone absorption was solubility and dissolution rate limited. However, in the fed state, higher bile salt solubilization led to more rapid dissolution with predominant absorption in the upper gastrointestinal tract, resulting in increased susceptibility to first-pass gut extraction; this accounts for the lack of correlation between Cmax and AUC for omaveloxolone.

Immunogenicity and safety of different dose levels of Ad26.RSV.preF/RSV preF protein vaccine in adults aged 60 years and older: A randomized, double-blind, placebo-controlled, phase 2a study

BackgroundRespiratory syncytial virus (RSV) can cause severe illness in older adults. A combination vaccine containing Ad26.RSV.preF and purified recombinant RSV preF protein has previously demonstrated efficacy and tolerability in older adults. We report results of a dose-ranging study to determine immunogenicity and safety of different doses of the Ad26.RSV.preF component in the combined Ad26.RSV.preF/RSV preF protein vaccine to support Ad26.RSV.preF drug product release and stability specifications. MethodsIn this randomized, double-blind, placebo-controlled, phase 2a study, adults aged ≥60 years in good or stable health were randomly assigned within 1 of 3 cohorts to receive either placebo or Ad26.RSV.preF/RSV preF protein, composed of different doses of Ad26.RSV.preF with a fixed dose of RSV preF protein (150 μg). Ad26.RSV.preF doses in Cohort 1 (4 dose-down groups) ranged from 3.7 × 109 to 1.0 × 1011 viral particles (vp). Doses in Cohorts 2 and 3 (2 dose-up groups, each) ranged from 1.0 to 1.6 × 1011 vp. Primary endpoints were immunogenicity (RSV preF protein antibody titers) for Cohort 1 and safety (solicited local and systemic adverse events [AEs] and unsolicited AEs) for Cohorts 2 and 3. Immunogenicity analyses (RSV preF protein antibody titers, RSV A2 neutralizing antibodies, and RSV-F–specific interferon-γ enzyme-linked immunosorbent spot) were performed on the day of vaccination and 14 days, 3 months, and 6 months postvaccination. Safety was monitored from vaccination until study end. ResultsOverall, 454 participants were enrolled and received 1 dose of study vaccine or placebo (Cohort 1, n = 226; Cohort 2, n = 124; Cohort 3, n = 104). No substantial differences in measured immune responses were observed between lower or higher Ad26.RSV.preF doses compared with Ad26.RSV.preF 1.0 × 1011 vp across all postvaccination time points. All Ad26.RSV.preF doses between 3.7 × 109 vp and 1.6 × 1011 vp were well tolerated, with no safety issues identified. ConclusionsResults of this dose-ranging study may be used to inform the refinement of Ad26.RSV.preF drug product release and stability specifications.Clinical Trial Registration:ClinicalTrials.gov Identifier: NCT04453202

Will Factor XI Inhibitors Replace Current Anticoagulants for Stroke Prevention in Atrial Fibrillation?

This review provides an overview of the factor XI (FXI) inhibitor hypothesis for the development of novel anticoagulants which may be safer to those currently used in clinical practice and describes preliminary clinical data from phase 2 dose-ranging studies of patients with atrial fibrillation. Recent data from phase 2 dose ranging studies demonstrate substantial reductions in bleeding with FXI pathway inhibition compared with currently approved anticoagulants. However, larger studies are necessary to demonstrate efficacy of FXI inhibition for stroke prevention in atrial fibrillation. FXI pathway inhibition holds great promise for revolutionizing the landscape of anticoagulation for atrial fibrillation, primarily by reducing bleeding risk; however, further data are necessary to demonstrate efficacy.

Phase 2 dose-ranging study to evaluate the efficacy and safety of liposomal irinotecan (LY01610) as a second-line treatment for patients with relapsed small cell lung cancer

This was a multicenter, single-arm dose-ranging phase 2 study aimed to assess the efficacy and safety of LY01610, a liposomal irinotecan, at various doses for patients with relapsed small cell lung cancer (SCLC). This study (NCT04381910) enrolled patients with relapsed SCLC at 10 hospitals across China, who have failed with previous platinum-based treatments. LY01610 was administered at doses of 60mg/m2, 80mg/m2, and 100mg/m2. Primary endpoints were investigator-assessed objective response rate (ORR) and investigator-assessed duration of response (DoR). Secondary endpoints included investigator-assessed disease control rate (DCR), investigator-assessed progression-free survival (PFS), overall survival (OS), and safety. From September 3, 2020 to March 3, 2022, a total of 66 patients were enrolled, with 6, 30, and 30 allocated to the 60mg/m2, 80mg/m2, and 100mg/m2 dose groups, respectively, with 68% (45/66) having a chemotherapy-free interval <90 days. In all 66 patients, the ORR was 32% (21/66, 95% confidence interval [CI], 21-44), with a median DoR of 5.2 months (95% CI, 3.0-8.3). Median PFS and OS were 4.0 (95% CI, 2.9-5.5) and 9.7 (95% CI, 7.2-12.3) months, respectively. The ORR of 60mg/m2, 80mg/m2, and 100mg/m2 dose group were 33% (2/6), 33% (10/30), and 30% (9/30), respectively. The median DoR of 60mg/m2, 80mg/m2, and 100mg/m2 dose group were 4.2 (95% CI, 2.8-not reached), 6.9 (95% CI, 2.5-9.9), and 4.0 (95% CI, 2.7-6.8) months, respectively. The incidence of ≥ grade 3 treatment-related adverse events (TRAEs) in the 60mg/m2, 80mg/m2, and 100mg/m2 dose group were 33% (2/6), 47% (14/30), and 50% (15/30), respectively. Themost common≥grade 3 TRAEs of all 66 patients were neutropenia (27%), leukopenia (24%) and anemia (15%). LY01610 exhibited promising clinical efficacy and manageable safety profiles in patients with relapsed SCLC, the 80mg/m2 dose group had the best benefit-risk ratio. This study was supported by Luye Pharma Group Ltd.

Efficacy and safety of Ibalizumab for the treatment of HIV-1 infected patients: A systematic review

Objectives: Human immunodeficiency virus (HIV) infection is a significant global health concern, due to the emerging complexity in the management of infection. The emergence of novel therapeutic agents, such as ibalizumab, has provided a ray of hope for individuals living with HIV. This systematic review provides a comprehensive analysis of the efficacy and safety of ibalizumab for the treatment of HIV-1-infected patients. Material and Methods: Using online medical literature databases and the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines, four of the 86 articles met the acceptance criteria to be analyzed. Details such as author name, year of publication, demographic characteristics, mode, and dose of drug administration, duration of treatment, comparator if any, baseline CD4 counts, and viral load, change in CD4 count and viral load, and the adverse events were noted in the studies. Results: The total number of patients enrolled in each study ranged from 22 to 82 with a median age ranging from 39 to 53. Except for the open-label dose-ranging cohort study, baseline CD4 counts and post-intervention CD4 counts were assessed in all the studies. The patients who received a higher dose of ibalizumab showed an early significant rise in CD4+T-cell count at week 16 and week 48. Although the viral reduction after ibalizumab injection increases from the dose of 3 mg/kg, it was noted that beyond 10mg/kg the viral load reduction was not increasing proportionately with 25 mg/kg. The adverse effects encountered among the four studies ranged from 45% to 91%. The commonly observed adverse effects were headache, diarrhea, nausea, fatigue, somnolence, and rash. Conclusion: Ibalizumab demonstrates promise as a therapeutic option for individuals with multidrug-resistant HIV-1. Its unique mechanism of action and positive impact on viral load reduction and CD4 cell counts make it a valuable addition to the armamentarium of HIV treatment options.

Indirect modeling of derived outcomes: Are minor prediction discrepancies a cause for concern?

It is often a goal of model development to predict data from which a variety of outcomes can be derived, such as threshold-based categorization or change from baseline (CFB) transformations. This approach can improve power or support multiple decisions. Because these derivations are indirectly predicted from the model, they are valuable tests for misspecification when used in visual or numeric predictive checks (V/NPCs). However, derived outcome V/NPCs (especially if primary or key secondary) are often overly scrutinized and held to an uncommon standard when comparing model predictions to point estimates, even if by conventional standards both the directly and indirectly modeled data are captured well. Here, simulations of directly modeled data were used to determine where apparent issues in V/NPCs of derived outcomes are expected. Two types of datasets were simulated: (1) a simple pre-post study and (2) pharmacokinetic/pharmacodynamic data from a dose-ranging study. A psoriasis exposure-response model case study was also assessed. V/NPCs were generated on the raw data, CFB data, and placebo-corrected CFB (dCFB) data, and binned summary statistics of the observed data for each trial were graded as being strongly or weakly supportive of a predictive model (within the interquartile range or the 95% central distribution of all simulated trials, respectively). In all cases, the strength of support in direct data V/NPCs was minimally related to that in derived outcome V/NPCs. There are myriad benefits to modeling the underlying data of a derived measure, and these results support caution in discarding adequate models based on overly strict derived measure predictive checks.

Safety and efficacy of subcutaneous iscalimab (CFZ533) in two distinct populations of patients with Sjögren's disease (TWINSS): week 24 results of a randomised, double-blind, placebo-controlled, phase 2b dose-ranging study

Sjögren's disease is a chronic autoimmune disease with an unmet need for targeted therapies. The aim of the TWINSS study is to evaluate the safety and efficacy of iscalimab, a monoclonal antibody against CD40, in patients with active Sjögren's disease. This randomised, double-blind, placebo-controlled, phase 2b study, conducted at 71 sites in 23 countries, enrolled patients aged 18 years or older fulfilling the American College of Rheumatology/European Alliance of Associations for Rheumatology (EULAR) 2016 criteria. In the dose-ranging cohort 1, patients with a EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score of 5 or higher and a EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score of 5 or higher were randomly assigned (1:1:1:1) to subcutaneous iscalimab 150 mg, 300 mg, 600 mg, or placebo. In the proof-of-concept cohort 2, patients with an ESSDAI score of less than 5, ESSPRI (dryness or fatigue) score of 5 or higher, and Impact of Dry Eye on Everyday Life score of 30 or higher were randomly assigned (1:1) to iscalimab 600 mg or placebo. The sponsor, investigator, site personnel, and patients were masked to the treatment assignment. The primary objectives were to demonstrate a dose-response relationship of iscalimab based on the change in ESSDAI from baseline to week 24 in cohort 1 by Multiple Comparison Procedure-Modelling (MCP-Mod), and to assess the effect of iscalimab 600 mg on ESSPRI at week 24 in cohort 2. All the efficacy analyses included all patients who were randomly assigned, and safety analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03905525), and is complete. Between Oct 1, 2019, and Feb 28, 2022, 460 patients were screened; 173 patients were assigned to cohort 1 (44 to iscalimab 150 mg, 43 to 300 mg, 43 to 600 mg, and 43 to placebo) and 100 to cohort 2 (50 to each group). In cohort 1, the MCP step showed a significant dose-response relationship for placebo-adjusted ESSDAI change from baseline in one of four models (Linlog model, one-sided p=0·0041). ESSDAI decreased from baseline to week 24 with all three doses of iscalimab; 150 mg and 600 mg doses showed statistically significant improvement (placebo-adjusted least squares [LS] mean difference -3·0 [95% CI -4·9 to -1·1]; p=0·0025 for 150 mg and -2·9 [-4·9 to -1·0]; p=0·0037 for 600 mg). In cohort 2, ESSPRI showed a trend towards improvement with iscalimab 600 mg (placebo-adjusted LS mean change from baseline -0·57 points [95% CI -1·30 to 0·15]; p=0·12). Serious adverse events were reported in nine patients in cohort 1 (one [2%] of 43 in the placebo group, one [2%] of 44 in the iscalimab 150 mg group, three [7%] of 42 in the 300 mg group, four [9%] of 44 in the 600 mg group) and four patients in cohort 2 (two [4%] of 50 in each group). No deaths occurred over the 24-week period. The study met the primary objective of demonstrating a significant dose-response relationship with iscalimab in terms of disease activity at week 24. Iscalimab was well tolerated and showed initial clinical benefit over placebo in two distinct populations of patients with Sjögren's disease, to be confirmed in larger trials. Novartis Pharma.

Pharmacokinetics and pharmacodynamics of itepekimab in adults with moderate-to-severe atopic dermatitis: Results from two terminated phase II trials.

Interleukin-33 (IL-33) is a proinflammatory alarmin cytokine released by damaged epithelial tissue cells that initiates and amplifies both type 1 and type 2 inflammatory cascades. A role for IL-33 in atopic dermatitis (AD; a chronic, relapsing type 2 inflammatory disease of the skin) has been proposed. Itepekimab is a novel human IgG4P monoclonal antibody against IL-33, currently in clinical development for chronic obstructive pulmonary disease (COPD). Two global phase II studies-a dose-ranging itepekimab monotherapy study (NCT03738423) and a proof-of-concept study of itepekimab alone and in combination with dupilumab (NCT03736967)-were conducted in patients with moderate-to-severe AD to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy; both studies were terminated following an interim analysis of the proof-of-concept study, which failed to demonstrate the efficacy of itepekimab. In these two studies, itepekimab exhibited linear and dose-proportional pharmacokinetics. Pharmacodynamics of total IL-33 indicated that itepekimab saturated binding to the target in serum at 300 mg q2w and q4w doses, and decreased blood eosinophil counts. Concentration-time profiles of itepekimab and total IL-33 were similar for itepekimab with or without dupilumab, and between East Asian and non-East Asian subgroups. Itepekimab was generally well tolerated, both alone and in combination with dupilumab. The lack of clinical efficacy for itepekimab observed in these studies suggests that IL-33 may not be a key pathogenic driver in moderate-to-severe AD.

Ampicillin-sulbactam against Acinetobacter baumannii infections: pharmacokinetic/pharmacodynamic appraisal of current susceptibility breakpoints and dosing recommendations.

Sulbactam dosing for Acinetobacter baumannii infections has not been standardized due to limited available pharmacokinetics/pharmacodynamics (PK/PD) data. Herein, we report a comprehensive PK/PD analysis of ampicillin-sulbactam against A. baumannii pneumonia. Twenty-one A. baumannii clinical isolates were tested in the neutropenic murine pneumonia model. For dose-ranging studies, groups of mice were administered escalating doses of ampicillin-sulbactam. Changes in log10cfu/lungs relative to 0 h were assessed. Dose-fractionation studies were performed. Estimates of the percentage of of time during which the unbound plasma sulbactam concentrations exceeded the MIC (%fT > MIC) required for different efficacy endpoints were calculated. The probabilities of target attainment (PTA) for the 1-log kill plasma targets were estimated following clinically utilized sulbactam regimens. Dose-fractionation studies demonstrated time-dependent kill. Isolates resistant to both sulbactam and meropenem required three times the exposures to achieve 1-log kill; median [IQR] %fT > MIC of 60.37% [51.6-66.8] compared with other phenotypes (21.17 [16.0-32.9] %fT > MIC). Sulbactam standard dose (1 g q6h, 0.5 h infusion) provided >90% PTA up to MIC of 4 mg/L. Sulbactam 3 g q8h, 4 h inf provided greater PTA for isolates with sulbactam-intermediate susceptibility (8 mg/L, 100% versus 86% following the standard dose). Despite the higher exposure following 3 g q8h, 4 h inf, PTA was ≤57% among sulbactam-resistant/meropenem-resistant isolates. Sulbactam standard dose is a valuable regimen across sulbactam-susceptible isolates while the high-dose extended-infusion provides additional benefit against sulbactam-intermediate isolates. Given that most of the sulbactam-resistant A. baumannii isolates are meropenem-resistant, high-dose prolonged-infusion regimens are not expected to be effective as monotherapy against infections due to these isolates.

Efficacy of epetraborole against Mycobacteroides abscessus in a mouse model of lung infection.

Mycobacteroides abscessus (Mab or Mycobacterium abscessus) is a fast-growing mycobacterium that is ubiquitous in the environment and can cause opportunistic disease in people with lung comorbidity and immunodeficiency. There are no Food and Drug Administration-approved drugs for this disease, and repurposed antibiotics have a poor microbiological response. To address the need for effective new antibiotics, we determined the efficacy of epetraborole (EBO) against three Mab clinical isolates in a mouse model of lung Mab infection. Reduction in lung Mab burden over 4 weeks of treatment was the study end point. EBO was administered orally once daily at doses of 25 and 50 mg/kg, which achieved exposures approximating the once-daily dosing of 250 mg and 500 mg, respectively, in humans. EBO administration led to a gradual reduction in the lung Mab burden. After 4 weeks of treatment, the efficacies of 25 and 50 mg/kg EBO against isolates ATCC 19977 and M9501 were comparable. However, against isolate M9530, 50 mg/kg EBO was more efficacious than 25 mg/kg and comparable with parenteral imipenem, one of the most efficacious antibiotics against Mab. We also undertook a dose-ranging study by evaluating the efficacies of once-daily oral administration of 0.5, 5, 10, 25, and 100 mg/kg EBO against M9501 over 4 weeks. Once-daily oral 100 mg/kg EBO was as effective as twice-daily 100 mg/kg imipenem injection. Our study suggests that EBO could address the unmet need for effective oral treatment options for Mab lung disease, given the high rates of Mab drug resistance and limited tolerable intravenous options.

Dupilumab in Adults With Moderate to Severe Atopic Dermatitis

Moderate to severe atopic dermatitis (AD) is a chronic inflammatory skin disease that often requires continuous long-term systemic management. Long-term safety and efficacy data for treatment options are critically important. To assess the safety and efficacy of dupilumab treatment for up to 5 years in adults with moderate to severe AD. The 5-year LIBERTY AD open-label extension study was conducted from September 2013 to June 2022 at 550 sites in 28 countries. The study enrolled adult patients with moderate to severe AD who had participated in previous dupilumab clinical trials. Data were analyzed from August 2022 to February 2023. At enrollment, patients initiated a regimen of subcutaneous dupilumab, 200 mg, weekly (400-mg loading dose). The regimen was amended in June 2014 to dupilumab, 300 mg, weekly (600-mg loading dose) based on a dose-ranging study and again in November 2019 to dupilumab, 300 mg, every 2 weeks to align with the regulatory regimen approvals. The primary end points were the incidence and rate of treatment-emergent adverse events (TEAEs). Key secondary end points included incidence and rate of serious TEAEs and adverse events of special interest, proportion of patients achieving an Investigator's Global Assessment (IGA) score of 0 or 1 (clear or almost clear), and proportion of patients with 75% or more improvement in the Eczema Area and Severity Index (EASI) from the parent study baseline. A total of 2677 patients were enrolled and treated in the open-label extension study; 1611 (60.2%) were male, and the mean (SD) age was 39.2 (13.4) years. A total of 334 patients (12.5%) completed treatment up to week 260. The most common reasons for withdrawal were due to regulatory approval of dupilumab in compliance with the study protocol (810 of 1380 [58.7%]), patient withdrawal (248 of 1380 [18.0%]), and adverse events (116 of 1380 [8.4%]). Exposure-adjusted rates of TEAEs were generally stable or declined throughout the study. Common TEAEs (incidence of 5% or greater) included nasopharyngitis, worsening AD, upper respiratory tract infection, conjunctivitis, conjunctivitis allergic, headache, oral herpes, and injection-site reaction. At week 260, 220 of 326 patients (67.5%) achieved an IGA score of 0 or 1 and 288 of 324 (88.9%) achieved 75% or greater improvement in the EASI. The mean (SD) EASI score was 16.39 (14.60) at baseline and 2.75 (5.62) at end of study. In this study, there was sustained safety and efficacy of continuous long-term dupilumab treatment for adults with moderate to severe AD.

Preliminary investigation of the safe dose of oleandrin when administered orally to Beagles.

The purpose of the study reported herein was to determine the dose of oleander extract and oleandrin (the key pharmacologically active constituent) that could be safely administered PO to dogs. 42 purebred Beagle dogs were used to study an extract of Nerium oleander. 3 studies were performed in 42 purebred young adult (ages 12 months or older) Beagle dogs using a supercritical fluid extract of N oleander leaves. The first study was an 8-day initial dose-ranging study in 2 dogs, a second 7-day repeat-dosing study was performed in 4 dogs, and the final study was performed in 32 dogs where test subjects were given extract or placebo once daily for 28 consecutive days via oral (gavage) administration followed by a 14-day recovery period. At 2.3 µg/kg of oleandrin, there were no observable adverse effects during the duration of the study. Adverse effects were not seen until doses exceeded 6.9 µg/kg of oleandrin, at which time mild, reversible clinical signs were noted. However, a dose > 460 µg of oleandrin/kg was fatal in 1 of 2 dogs in this study. The studies reported here, taken in totality, suggest that doses exceeding 6.9 µg/kg of oleandrin may be associated with cardiac abnormalities. An estimated no treatment effective adverse event oral dose of oleandrin appears to be 4.6 µg of oleandrin/kg. Higher doses may be tolerable but should be used with appropriate monitoring.

Disitamab vedotin, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpression and HER2-low advanced breast cancer: a phase I/Ib study.

Disitamab vedotin (DV; RC48-ADC) is an antibody-drug conjugate comprising a human epidermal growth factor receptor 2 (HER2)-directed antibody, linker and monomethyl auristatin E. Preclinical studies have shown that DV demonstrated potent antitumor activity in preclinical models of breast, gastric, and ovarian cancers with different levels of HER2 expression. In this pooled analysis, we report the safety and efficacy of DV in patients with HER2-overexpression and HER2-low advanced breast cancer (ABC). In the phase I dose-escalation study (C001 CANCER), HER2-overexpression ABC patients received DV at doses of 0.5-2.5 mg/kg once every two weeks (Q2W) until unacceptable toxicity or progressive disease. The dose range, safety, and pharmacokinetics (PK) were determined. The phase Ib dose-range and expansion study (C003 CANCER) enrolled two cohorts: HER2-overexpression ABC patients receiving DV at doses of 1.5-2.5 mg/kg Q2W, with the recommended phase 2 dose (RP2D) determined, and HER2-low ABC patients receiving DV at doses of 2.0 mg/kg Q2W to explore the efficacy and safety of DV in HER2-low ABC. Twenty-four patients with HER2-overexpression ABC in C001 CANCER, 46 patients with HER2-overexpression ABC and 66 patients with HER2-low ABC in C003 CANCER were enrolled. At 2.0 mg/kg RP2D Q2W, the confirmed objective response rates were 42.9% (9/21; 95% confidence interval [CI]: 21.8%-66.0%) and 33.3% (22/66; 95% CI: 22.2%-46.0%), with median progression-free survival (PFS) of 5.7 months (95% CI: 5.3-8.4 months) and 5.1 months (95% CI: 4.1-6.6 months) for HER2-overexpression and HER2-low ABC, respectively. Common (≥5%) grade 3 or higher treatment-emergent adverse events included neutrophil count decreased (17.6%), gamma-glutamyl transferase increased (13.2%), asthenia (11.0%), white blood cell count decreased (9.6%), peripheral neuropathy such as hypoesthesia (5.9%) and neurotoxicity (0.7%), and pain (5.9%). DV demonstrated promising efficacy in HER2-overexpression and HER2-low ABC, with a favorable safety profile at 2.0 mg/kg Q2W.

Once-daily upadacitinib versus placebo in adults with extensive non-segmental vitiligo: a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-ranging study

Janus kinase (JAK) inhibition is a promising approach for treating vitiligo. We aimed to assess the efficacy and safety of upadacitinib, an oral selective JAK inhibitor, in adults with non-segmental vitiligo. This was a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-ranging study completed at 33 clinical centres in the United States, Canada, France, and Japan. Eligible patients were aged 18-65 years with non-segmental vitiligo and had a Facial Vitiligo Area Scoring Index (F-VASI) ≥0.5 and a Total Vitiligo Area Scoring Index (T-VASI) ≥5. Patients were randomly assigned (2:2:2:1:1) using an interactive response technology to receive upadacitinib 6mg (UPA6), upadacitinib 11mg (UPA11), upadacitinib 22mg (UPA22), or placebo (PBO; preassigned to switch to either UPA11 or UPA22 in period 2) once daily for 24 weeks (period 1). For weeks 24-52 (period 2), patients randomly assigned to upadacitinib continued their treatment, and patients receiving PBO switched to their preassigned upadacitinib dose in a blinded fashion. The primary endpoint was the percent change from baseline in F-VASI at week 24. Efficacy was analysed in the intention-to-treat population, and safety was examined in all randomly assigned patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT04927975. Between June 16, 2021, and June 27, 2022, 185 patients (including 115 [62%] who were female and 70 [38%] who were male) were randomly assigned to UPA6 (n=49), UPA11 (n=47), UPA22 (n=43), or PBO (n=46). At week 24, the LS mean difference versus PBO in the percent change from baseline in F-VASI was-7.60 (95% CI-22.18 to 6.97; p=0.3037) for UPA6,-21.27 (95% CI-36.02 to-6.52; p=0.0051) for UPA11, and-19.60 (95% CI-35.04 to-4.16; p=0.0132) for UPA22. The LS mean difference versus PBO in the percent change from baseline in T-VASI was-7.45 (95% CI-16.86 to 1.96; p=0.1198) for UPA6,-10.84 (95% CI-20.37 to-1.32; p=0.0259) for UPA11 and-14.27 (95% CI-24.24 to-4.30; p=0.0053) for UPA22. Ongoing treatment with upadacitinib induced continuous skin repigmentation over time without reaching a plateau through week 52. The rates for study drug discontinuation and serious treatment-emergent adverse events (TEAEs) were higher in the UPA22 group than in the UPA11 and UPA6 groups. Eight serious TEAEs, including one death of unknown cause and one case of infiltrating lobular breast carcinoma, were reported through 52 weeks; only two serious TEAEs (coronary artery arteriosclerosis [UPA6 (n=1)] and non-fatal ischemic stroke [UPA11 (n=1)]) were deemed by the investigator to have a reasonable possibility of being related to study drug. The one case of breast cancer in the UPA11 group was deemed unrelated to study drug, and the one death of unknown cause in the UPA22 group was reviewed and adjudicated and was deemed to be unrelated to study drug. The most common TEAEs were COVID-19, headache, acne, and fatigue. No new safety signals were observed. Upadacitinib monotherapy led to substantial repigmentation of both facial and total body vitiligo lesions and may offer an effective treatment option for adults with extensive non-segmental vitiligo. Based on these findings, upadacitinib 15mg is being investigated in adults and adolescents with non-segmental vitiligo in an ongoing phase 3 randomised controlled trial. AbbVie Inc.