OBJECTIVES:Multicentric Castleman disease (MCD) is a rare lymphoproliferative disorder characterized by multifocal lymphadenopathy and systemic inflammatory symptoms. This single-arm, prospective, observational, postmarketing surveillance (UMIN000023071) assessed the real-world effectiveness and safety of tocilizumab in Japanese patients with MCD. METHODS:Patients with MCD received tocilizumab intravenous infusion 8 mg/kg every 2 weeks for up to 3 years. Effectiveness outcomes included enlarged lymph node regression; improvement in laboratory findings, associated symptoms, and organ involvement; and change in corticosteroid doses. Safety was assessed through adverse events (AEs). RESULTS:A total of 342 patients were included. Tocilizumab was continued for >152 weeks in 70.1% of patients. After treatment, 58.9% of patients showed lymph node regression. Laboratory test values were improved, and most evaluable patients reported improvements in associated symptoms, including night sweats, anorexia, fever, and fatigue. Organ involvement, including pulmonary disease, rash, and hepatosplenomegaly, was 'improved' or 'stable' in more than half of evaluable patients. Tocilizumab treatment resulted in corticosteroid dose reduction. The most commonly reported AEs were infections and infestations; respiratory, thoracic, and mediastinal disorders; and gastrointestinal disorders. CONCLUSIONS:The effectiveness and safety of tocilizumab in Japanese patients with MCD was confirmed for up to 3 years, without new safety concerns.
Neuromyelitis optica spectrum disorder (NMOSD) is a chronic disorder with a relapsing–remitting disease course that impacts patients' quality of life. Oral glucocorticoids (OGCs) have been the standard of care for NMOSD in Japan; however, their chronic use is associated with adverse events (AEs). We investigated the causal relationship between NMOSD symptoms and patient-determined OGC-related AEs (Pd-OGC-AEs) and their impact on patients' daily living and emotions. This online interview survey was conducted between August and December 2023. Adult Japanese patients with aquaporin-4 immunoglobulin G–seropositive NMOSD and currently taking or having a history of OGC use were asked about their episodes of NMOSD symptoms and Pd-OGC-AEs experienced to date and their impact on daily living and emotions. A qualitative analysis was performed by coding and categorizing data and assessing the causality of symptoms and AEs with patients' daily living and emotions, and a conceptual framework was developed. Fifteen patients (14 females; median [range] age, 53 [23–66] years) were included. Neurological findings were normal in four patients, with very mild symptoms in seven patients and mild disability and relatively severe impairment in two patients each. NMOSD symptoms such as visual and sensory disturbances and patient-determined OGC-related Cushing's syndrome affected patients' daily living and emotions by increasing their dependence on others and made them feel hopeless. NMOSD symptoms and Pd-OGC-AEs adversely impacted patients' daily living and emotions. Based on these results, a survey questionnaire is being planned to assess patient preferences for tailored NMOSD treatment options.
JO40295 (jRCT2080223801) evaluated the efficacy and safety of subcutaneous (SC) mosunetuzumab, in combination with lenalidomide and as monotherapy, in Japanese patients with relapsed/refractory (R/R) follicular lymphoma (FL). We report outcomes from the interim analysis of the FLMOON-2 (≥ 1 prior therapy; mosunetuzumab plus lenalidomide) and primary analysis of the FLMOON-3 (≥ 2 prior therapies; mosunetuzumab monotherapy) cohorts. Mosunetuzumab SC was administered with Cycle (C)1 step-up dosing in both cohorts: C1 Day (D)1, 5 mg; C1D8, D15 and C2 onwards, 45 mg. In FLMOON-2, oral lenalidomide was administered from C2 onwards, on D1–21 of each cycle. Treatment was administered up to C12 in FLMOON-2 and C8 or C17 in FLMOON-3. The primary endpoint was independent review facility-assessed complete response (CR) rate. At the clinical cut-off date (FLMOON-2: April 4, 2024; FLMOON-3: March 4, 2024), in the efficacy-evaluable populations, CR rate was 92.3
Cyclic peptides containing N-alkylated amino acids represent a promising therapeutic modality, offering access to intracellular targets previously considered "undruggable" and potential for oral administration. The N-alkyl groups (e.g., N-methyl groups) play an important role in enhancing the pharmacological properties of these peptides by improving cell membrane permeability and metabolic stability; however, the efficient synthesis of N-alkyl-rich peptides has remained an underdeveloped area of research. Herein, we report two types of peptide fragment coupling reactions developed toward the realization of highly convergent synthesis of N-alkyl-rich peptides. These two reactions enable fragment coupling of diverse N-methylated substrates with exceptional resistance to epimer formation─a challenge that has proven difficult with established methods. The first reaction utilizing pivaloyl mixed anhydride under liquid-liquid biphasic conditions addresses the substrate combinations with N-methylation at the amino terminus. The second reaction utilizing 2-hydroxypyridine N-oxide (HOPO) and Oxyma or Oxyma-B addresses the substrate combinations with N-methylation at both amino and carboxyl termini. Together, these two complementary reactions represent an advancement in the synthesis of N-alkyl-rich peptides.
