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Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension. We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro-B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit. A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, -0.3 to 3.5) in the placebo group. The Hodges-Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure. In patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.).

Patients with pulmonary arterial hypertension were randomly assigned to receive sotatercept at a dose of 0.3 mg per kilogram or 0.7 mg per kilogram or placebo, in addition to standard therapy. At 24 weeks, both sotatercept groups had a greater reduction in pulmonary vascular resistance than the placebo group.

Introduction. Hypoglycemic drugs affect the bone quality and the risk of fractures in patients with type 2 diabetes mellitus (T2DM). We aimed to investigate the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and insulin on bone mineral density (BMD) in T2DM. Methods. In this single-blinded study, a total of 65 patients with T2DM were randomly assigned into four groups for 52 weeks: the exenatide group (n=19), dulaglutide group (n=19), insulin glargine group (n=10), and placebo (n=17). General clinical data were collected, and BMD was measured by dual-energy X-ray absorptiometry. Results. Compared with baseline, the glycosylated hemoglobin (HbA1c) decreased significantly in the exenatide (8.11±0.24% vs. 7.40±0.16%, P=0.007), dulaglutide (8.77±0.37% vs. 7.06±0.28%, P<0.001), and insulin glargine (8.57±0.24% vs. 7.23±0.25%, P<0.001) groups after treatment. In the exenatide group, the BMD of the total hip increased. In the dulaglutide group, only the BMD of the femoral neck decreased (P=0.027), but the magnitude of decrease was less than that in the placebo group; the BMD of L1-L4, femoral neck, and total hip decreased significantly (P<0.05) in the placebo group, while in the insulin glargine group, the BMD of L2, L4, and L1-4 increased (P<0.05). Compared with the placebo group, the BMD of the femoral neck and total hip in the exenatide group and the insulin glargine group were increased significantly (P<0.05); compared with the exenatide group, the BMD of L4 in the insulin glargine group was also increased (P=0.001). Conclusions. Compared with the placebo, GLP-1RAs demonstrated an increase of BMD at multiple sites of the body after treatment, which may not exacerbate the consequences of bone fragility. Therefore, GLP-1RAs might be considered for patients with T2DM. This trial is registered with ClinicalTrials.gov NCT01648582.

Therapeutic agents targeting the tumor necrosis factor (TNF) superfamily cytokines B‐cell activating factor (BAFF, BLyS) and/or A PRoliferation Inducing Ligand (APRIL) have demonstrated clinical effectiveness in multiple autoimmune diseases, such as systemic lupus erythematosus, lupus nephritis, and immunoglobulin A nephropathy (IgAN). However, their clinical utility can often be limited by incomplete and/or prolonged times to clinical response and inconvenient dosing regimens, which may be improved by more potent dual inhibition of both cytokines. Povetacicept (ALPN‐303; TACI vTD‐Fc) is a crystallizable fragment (Fc) fusion protein of an engineered transmembrane activator and CAML interactor (TACI) domain which mediates more potent inhibitory activity than wild‐type TACI‐Fc or BAFF‐ or APRIL‐specific antibodies and demonstrates superior pharmacokinetic and pharmacodynamic activity in multiple preclinical disease models. In this first‐in‐human study in healthy adults, povetacicept was well‐tolerated as single ascending doses of up to 960 mg administered intravenously or subcutaneously. Dose‐dependent pharmacokinetics were observed. Coverage of BAFF and APRIL was observed for 2–3 weeks and ≥4 weeks after doses of 80 mg and ≥240 mg, respectively. Maximal pharmacodynamic effects were observed at dose levels ≥80 mg for a single dose, associated with on‐target reductions in antibody‐secreting cells as well as in all circulating immunoglobulin isotypes, including the IgAN disease‐related biomarker galactose‐deficient‐immunoglobulin A1 (Gd‐IgA1), and were superior to results reported for wild‐type TACI‐Fc. These data strongly support further development of povetacicept for the treatment of B‐cell‐mediated automimmune diseases.

To assess the renoprotective effects of dulaglutide and identify mechanisms of action in patients with type 2 diabetes and diabetic kidney disease (DKD). Outpatients/ambulant patients at the Department of Endocrinology, Affiliated Hospital of Xuzhou Medical University between October 2021 and July 2023, with type 2 diabetes and DKD, a urinary albumin-to-creatinine ratio (UACR) ≥ 3 mg/mmol and who were receiving hypoglycemic agents were prescribed dulaglutide at a dose rate of 0.75 - 1.5 mg once weekly (intervention group; n = 70). Patients receiving hypoglycemic agents other than glucagon-like peptide-1 (GLP-1) receptor agonists and who were not prescribed dulaglutide constituted the control group (n = 65). Observations/outcomes: The primary outcome was a change in the UACR and biomarkers of epithelial-mesenchymal transition (EMT) determined after 12 months of intervention treatment. Adverse events (estimates of tolerability and safety) were recorded during treatment and a follow-up period of 12 months. UACR changes in the intervention group compared to the control group were significantly lower (p < 0.01 at 6 months and p < 0.05 at 12 months). The frequency of gastrointestinal adverse events in the two groups were not significantly different, and there were no significant increases in the number of hypoglycemic events. Dulaglutide significantly increased the epithelial marker E-cadherin and inhibited the mesenchymal marker periostin. It is concluded that dulaglutide causes significant reductions in urinary albumin and modulates EMT-related proteins thereby ameliorating the decline in kidney function in patients with type 2 diabetes and DKD.

Conventional dendritic cells subtype 1 (cDC1) play a vital role in the priming and expansion of tumor‐specific CD8+ T cells and their recruitment to tumor microenvironment. However, cDC1s are often underrepresented in the microenvironment. Systemic administration of Fms‐like tyrosine kinase 3 ligand, a hematopoietic growth factor that binds to FLT3 on myeloid and lymphoid progenitor cells, leads to cDC1 expansion in the periphery and recruitment into the microenvironment. FLT3 pathway stimulation using GS‐3583, a novel FLT3 agonistic Fc fusion protein, has the potential to promote T‐cell mediated antitumor activity. This was a first‐in‐human, placebo‐controlled study of GS‐3583 in healthy participants to evaluate the safety, pharmacokinetics (PK), and pharmacodynamic (PD) of escalating single doses (75–2000 μg) of GS‐3583. Each dose cohort enrolled 8–12 healthy participants who received GS‐3583 or placebo as single IV infusion at 3:1 ratio. As part of the PD evaluation, the changes in the number of cDC1 cells were investigated. GS‐3583 was well‐tolerated in healthy participants up to the highest evaluated dose (2000 μg). There have been no serious or grade III or higher adverse events. PK analysis suggested a dose‐dependent increase in GS‐3583 exposure with target‐mediated disposition characteristics at low doses. PD analysis shows that administration of GS‐3583 resulted in transient, dose‐dependent increases in cDC1 cells that returned to baseline within 3 weeks of drug administration. The pharmacokinetics and pharmacodynamics of GS‐3583 following single dosing were characterized in this study which enabled subsequent phase Ib assessments in patients with advanced solid tumors.

Modakafusp alfa (TAK‐573) is a novel, first‐in‐class fusion protein of a humanized anti‐CD38 IgG4 kappa antibody fused to attenuated human interferon alfa‐2b. It acts as an agonistic innate immunity enhancer through targeted interferon (IFN) signaling and has been investigated as an immune‐oncology therapeutic agent in patients with relapsed/refractory multiple myeloma (RRMM). Population PK analysis and sequential PK‐PD analysis of serum M‐protein (MP) as a primary marker of tumor burden in RRMM were conducted using dose escalation (Part 1) and dose expansion (Part 2) data from 96 RRMM patients enrolled in the Phase 1/2 iinnovate‐1 trial. After exploring various structural PK models with different levels of mechanistic complexity, a Michaelis–Menten approximation model that included an anti‐drug antibody (ADA) binding model adequately captured the nonlinear PK of modakafusp alfa and the apparent time‐varying impact of ADA on the PK. Body weight was a significant predictor of central volume of distribution (exponent of 0.51) but was not predictive of elimination‐related parameters given both catabolic and likely target‐mediated elimination processes. Serum MP data from patients evaluable at baseline were adequately characterized using the Claret tumor growth inhibition and drug resistance model, with antitumor drug effect using an Emax model. The population PK and PK‐PD modeling results supported model‐informed drug development for modakafusp alfa, including the switch from weight‐based to fixed dosing and the selection of two fixed doses for the randomized dose extension (Part 3) phase of the trial to inform future optimal dose selection, which is consistent with the Project Optimus paradigm.

Background Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the treatment of type 2 diabetes mellitus are known to delay gastric emptying (GE). The potential effect of the GLP-1 RA dulaglutide on the pharmacokinetics (PK) of four orally administered drugs and on the pharmacodynamic (PD) effect of warfarin was investigated. Methods In four separate clinical pharmacology studies, digoxin, warfarin, atorvastatin and Ortho-Cyclen ® were orally administered to healthy subjects with and without a subcutaneous dose of dulaglutide 1.5 mg. The effect of dulaglutide coadministration was assessed based on the PK parameters of key analytes. For warfarin PD, the effect of dulaglutide on the international normalized ratio (INR) was evaluated. Results Areas under the concentration–time curves (AUCs) with and without dulaglutide were similar for all analytes except atorvastatin, where it was reduced by 21%. Maximum concentrations ( C max ) were generally lower following coadministration with dulaglutide, with statistically significant reductions (90% confidence intervals of geometric least squares means ratios outside 0.80–1.25) for all analytes except R-warfarin. For all analytes, there was a general trend for the time to C max ( t max ) to increase following coadministration with dulaglutide. For warfarin, dulaglutide coadministration had no statistically significant effect on the maximum INR (INR max ); however, a 2% increase in area under the INR curve (AUC INR ) was observed. Conclusions Dulaglutide did not affect the absorption of the tested medications to a clinically relevant degree. Based on the PK and PD evaluations, no dose adjustments for digoxin, warfarin, atorvastatin and Ortho-Cyclen ® are recommended when coadministered with dulaglutide. Clinical trial registration numbers NCT01458210, NCT01436201, NCT01432938, and NCT01250834.

Immune thrombocytopenia (ITP) is a disease which sees one-third of patients failing first and subsequent therapeutic approaches, including splenectomy. Thrombopoietin-receptor agonists (TPO-RAs) are recommended for adults who relapse after splenectomy or who have contraindications for splenectomy. In this multicenter study, a total of 124 patients were retrospectively evaluated: 55 (44.3 %) were treated by romiplostim and 69 (55.6 %) by eltrombopag. Mean age, number of young patients (<60 years), time from primary diagnosis of ITP to TPO-RA treatment, and previous lines of therapy were similar in both groups. The overall response rate was 80 % (44/55) for romiplostim and 94.2 % (65/69) for eltrombopag; the duration of response and the time to response were similar ( p  = NS). The response rate to both drugs in non-splenectomized patients was higher than that of splenectomized patients ( p  < 0.05). The mean duration of response was 30 months for romiplostim and 15 months for eltrombopag, due to later commercialization of eltrombopag. Failure was the most frequent cause of discontinuation. Thrombotic events were the most consistent adverse events and were recorded in 2 and 3 % of patients treated by romiplostim and eltrombopag, respectively. In conclusion, romiplostim and eltrombopag are effective in the majority of patients with chronic ITP who failed several lines of therapy; whether TPO-RAs could substitute splenectomy is under discussion and studies are warranted.