Astellas Pharma (Netherlands)

ASP8302 is an orally administered positive allosteric modulator of the muscarinic M3 receptor. Two Phase 1 studies were conducted, a first-in-human study in Europe and a Japanese phase 1 study. Both were randomized, participant- and investigator-blinded, placebo-controlled, single and multiple ascending oral doses, parallel group, clinical studies in healthy volunteers. Both studies evaluated safety and pharmacokinetics and also included salivary secretion and pupil diameter as pharmacodynamic assessments. There were no deaths, serious adverse events, or treatment-emergent adverse events reported leading to study discontinuation. There were no clinically relevant findings in any of the laboratory, vital signs, electrocardiogram assessments, or photosensitivity testing following multiple administration of up to 150 mg or up to 140 mg once daily for 14 days in the European first-in-human and Japanese Phase 1 study, respectively. The pharmacokinetics of ASP8302 were approximately linear over the dose range studied. There was no evidence of drug accumulation upon repeated dosing. In both studies, ASP8302 showed a dose-dependent pharmacodynamic effect on saliva production at doses from 100 mg onward, which was maintained during repeated dosing. No effect was observed on pupil diameter. These data supported progression of ASP8302 into Phase 2 clinical trials for further clinical development.

BackgroundIntraoperative ureteral injury, a serious complication of abdominopelvic surgeries, can be avoided through ureter visualization. Near-infrared fluorescence imaging offers real-time anatomical visualization of ureters during surgery. Pudexacianinium (ASP5354) chloride is an indocyanine green derivative under investigation for intraoperative ureter visualization during colorectal or gynecologic surgery in adult and pediatric patients.MethodsIn this phase 2 study (NCT04238481), adults undergoing laparoscopic colorectal surgery were randomized to receive one intravenous dose of pudexacianinium 0.3 mg, 1.0 mg, or 3.0 mg. The primary endpoint was successful intraoperative ureter visualization, defined as observation of ureter fluorescence 30 min after pudexacianinium administration and at end of surgery. Safety and pharmacokinetics were also assessed.ResultsParticipants received pudexacianinium 0.3 mg (n = 3), 1.0 mg (n = 6), or 3.0 mg (n = 3). Most participants were female (n = 10; 83.3%); median age was 54 years (range 24–69) and median BMI was 29.3 kg/m2 (range 18.7–38.1). Successful intraoperative ureter visualization occurred in 2/3, 5/6, and 3/3 participants who received pudexacianinium 0.3 mg, 1.0 mg, or 3.0 mg, respectively. Median intensity values per surgeon assessment were 1 (mild) with the 0.3-mg dose, 2 (moderate) with the 1.0-mg dose, and 3 (strong) with the 3.0-mg dose. A correlation was observed between qualitative (surgeon’s recognition/identification of the ureter during surgery) and quantitative (video recordings of the surgeries after study completion) assessment of fluorescence intensity. Two participants experienced serious adverse events, none of which were drug-related toxicities. One adverse event (grade 1 proteinuria) was related to pudexacianinium. Plasma pudexacianinium concentrations were dose-dependent and the mean (± SD) percent excreted into urine during surgery was 22.3% ± 8.0% (0.3-mg dose), 15.6% ± 10.0% (1.0-mg dose), and 39.5% ± 12.4% (3.0-mg dose).ConclusionsIn this study, 1.0 and 3.0 mg pudexacianinium provided ureteral visualization for the duration of minimally invasive, laparoscopic colorectal procedures and was safe and well tolerated.

Targeted therapy in oncology brings with it the promise to maximize cancer cell cytotoxicity with minimal off-target effects. Antibody-drug conjugates (ADCs), an important group of such targeted agents, consist of a monoclonal antibody conjugated to a potent cytotoxic drug. In the field of leukemia, ADCs form an important component of therapeutic arsenal through the use of gemtuzumab ozogamicin in acute myeloid leukemia and inotuzumab ozogamicin (InO) in B-cell acute lymphoblastic leukemia, 2 approved agents. A recombinant fusion protein, tagraxofusp, which function similar to ADC, has gained approval for therapy in blastic plasmacytic dendritic cell neoplasm. The use of such agents as monotherapy or as part of a combination therapy has led to improved response rates and outcomes in certain specific disease subtypes and has led to further studies to identify novel cellular targets and improved delivery of cytotoxic agents using ADC. In this review, we will discuss about ADCs in myeloid leukemia and understand their development and current use in the field.

There is limited information on the clinical use of Janus kinase inhibitors (JAKis) for rheumatoid arthritis treatment in Japan. The aim of this study was to identify disease-modifying antirheumatic drug (DMARD) treatment patterns in Japan. This retrospective, longitudinal study extracted data from the Japan Medical Data Center database. Patients with rheumatoid arthritis diagnosis were enrolled 2016-19, during which patients had a first prescription of a major DMARD, split into six mutually exclusive classes: methotrexate (MTX); other conventional synthetic DMARDs; tumour necrosis factor alpha inhibitors; cytotoxic T-lymphocyte-associated antigen-4-immunoglobulin; anti-interleukin-6 receptor therapies; and JAKis. The primary objective was to describe DMARD treatment patterns, especially for JAKis. Overall, 10,399 patients were included in the analysis. The most common treatments were MTX, other conventional synthetic DMARDs, and tumour necrosis factor alpha inhibitors. The total number of JAKi prescriptions increased approximately 8-fold during 2016-19. Most (61.1%) patients who received JAKis had prior MTX or tumour necrosis factor alpha inhibitor treatment. The duration of JAKi treatment was longer than for biologics and other conventional synthetic DMARDs and comparable to that of MTX. The sequence of drug class prescriptions for rheumatoid arthritis in Japan during 2016-19 followed clinical guidelines. Over this period, JAKis were increasingly used as a second-line treatment following MTX.

Abstract BACKGROUND AND AIMS Patients with late-stage chronic kidney disease (CKD) who are non–dialysis-dependent (NDD) or incident to dialysis (ID) (e.g. initiated dialysis within the last 4 months) or dialysis-dependent (DD) represent a vulnerable population at increased risk for morbidity and mortality despite significant clinical advancements in recent years. The safety of roxadustat in patients with NDD or ID-DD CKD requires further elucidation. METHOD In this post-hoc exploratory analysis, safety results from eligible patients with anemia of CKD enrolled in four phase 3, randomized, open-label studies [NDD (DOLOMITES) or ID-DD (SIERRAS, HIMALAYAS, ROCKIES)] were pooled and compared roxadustat to an erythropoiesis-stimulating agent (ESA). Endpoints were time to major adverse cardiovascular event [MACE; myocardial infarction, stroke and all-cause mortality (ACM)] and MACE+ (MACE plus congestive heart failure or unstable angina requiring hospitalization), ACM, and treatment-emergent adverse events (TEAEs). MACE and MACE + were evaluated for non-inferiority using hazard ratios (HRs) at 1.8 and 1.3-upper margins, respectively, and 95% confidence intervals (CIs). TEAEs were descriptively summarized. RESULTS In total, 2142 patients were evaluated (1083 roxadustat; 1059 ESA; 616 NDD; 1526 ID-DD). Roxadustat was non-inferior to ESA for risk of MACE [HR 0.79 (95% CI 0.61–1.02)] and MACE+ [HR 0.78, (95% CI 0.62–0.98)] with a consistent finding for ACM [HR 0.78 (95% CI 0.57–1.05)]. TEAEs were generally comparable between roxadustat and ESA groups, including any TEAE [incidence rate per 100 patient-exposure years (IR/100 PEY) 56.1 versus 53.5], TEAEs leading to discontinuation of study drug (IR/100 PEY 6.7 versus 5.1) and TEAEs leading to death (IR/100 PEY 6.9 versus 7.4). The most frequent (IR/100 PEY) TEAEs were hypertension (roxadustat 12.8, ESA 12.3), end-stage kidney disease (roxadustat 6.6, ESA 6.1), diarrhea (roxadustat 7.1, ESA 4.8) and hyperkalemia (roxadustat 4.3, ESA 4.8). CONCLUSION There was no evidence of an increased risk of cardiovascular events or mortality with roxadustat compared with ESA in patients with anemia who have NDD or ID-DD CKD. Although TEAE development occurred commonly in both the roxadustat and ESA groups, patients infrequently discontinued a study drug because of an adverse event.