Advances in Therapy最新文献

Introduction: Patients with intestinal failure caused by short bowel syndrome (SBS) are dependent on parenteral support (PS) for nutrition. Teduglutide, an analogue of glucagon-like peptide 2, has been shown to decrease reliance on PS with an acceptable safety profile in multiregional phase 3 clinical trials, but currently there are no reports examining treatment outcomes with teduglutide in the real-world population in Japan. This interim analysis of a 36-month post-marketing surveillance (PMS) reports the safety and effectiveness of teduglutide in adults and pediatric patients with SBS in Japan.

Methods: This 6-month analysis was conducted as part of a prospective, all-case, 36-month PMS of teduglutide (Takeda Pharmaceutical Company Limited) conducted in patients with SBS across 102 sites in Japan. All patients who started teduglutide treatment from August 2021 to August 2022 were enrolled. Safety and effectiveness were evaluated after 6 months of teduglutide treatment and compared with baseline.

Results: A total of 123 patients aged 2-83 years were included in the safety analysis, including 27 children (aged < 15 years). A total of 51 patients (44 adults, 7 children) reported 117 adverse drug reactions (ADRs). In adults, the most common ADRs were abdominal distension (10.42%), abdominal pain (10.42%), stoma complication (8.33%), and nausea (7.29%). In children, the most common ADR was abdominal pain (11.11%). In the effectiveness analysis, 11.9% (12/101) of patients were able to wean off PS and 42.4% (39/92) were able to achieve at least 20% reduction in their PS volume. The overall mean (standard deviation) change from baseline in the z-score of body weight in children (n = 20) was 0.185 (0.2964).

Conclusion: In this interim analysis of a 36-month PMS, teduglutide demonstrated an acceptable safety profile and promising effectiveness in patients with SBS.

Trial registration: ClinicalTrials.gov identifier, NCT05023382.

Introduction: Since 2020, several androgen receptor signaling inhibitors (ARSIs) have been approved for use among patients with metastatic castration-sensitive prostate cancer (mCSPC) in Japan. To evaluate how these approvals may have changed the mCSPC treatment landscape in Japan, we analyzed treatment patterns and time to treatment discontinuation (TTD) since 2020 in patients with mCSPC.

Methods: This retrospective cohort study utilized data from the Medical Data Vision health administrative database between May 2020 and March 2024. Study endpoints were patient characteristics at baseline, first-line, and subsequent-line treatment patterns; TTD of first-line therapies; and TTD of first-line ARSIs. Patient characteristics were analyzed descriptively. Hazard ratios (HRs) for TTD between treatment classes were calculated using an inverse probability of treatment weight-adjusted Cox proportional hazards model.

Results: Overall, 8830 patients with mCSPC were identified. Treatment with androgen-deprivation therapy (ADT) plus ARSI increased during follow-up, while treatment with ADT plus nonsteroidal antiandrogens (NSAAs) decreased. Transition from first- to second-line therapy occurred in approximately 32% of patients. Patients who received first-line ADT plus ARSI had a lower risk of treatment discontinuation compared with patients who received first-line ADT alone (adjusted HR 0.62, 95% CI 0.59-0.65) or ADT plus NSAA (adjusted HR 0.50, 95% CI 0.48-0.52). Among ARSIs, ADT plus enzalutamide had the longest median TTD.

Conclusion: Use of ARSIs for mCSPC is increasing, but ADT alone and ADT plus NSAA are still frequently used. The longer treatment duration among patients who received ARSIs indicates that treatment intensification with ARSIs is vital for mCSPC disease control.

Introduction: In Italy, real-world data on muscle-invasive bladder cancer (MIBC) are scanty. This analysis exploited administrative databases to describe the clinical characteristics and treatment outcomes of patients with MIBC.

Methods: Adults hospitalized for non-metastatic bladder cancer who underwent cystectomy in 2018 were proxied for MIBC. The following variables were examined: demographic and clinical characteristics, number of transurethral resections of the bladder tumor (TURBs) and time to cystectomy to discriminate de novo diagnoses from progressions; chemotherapy ± 6 months before/after cystectomy to distinguish neoadjuvant or adjuvant regimens; creatinine clearance (CrCl) as an indicator of renal function for cisplatin eligibility; disease-free survival (DFS) and overall survival (OS) using Kaplan-Meier method.

Results: Among 394 patients included, 79.4% were men; mean age was 72.5 years and Charlson comorbidity index (CCI) 0.6. Three hundred thirty-nine (86%) had ≥ 1 TURBs pre-cystectomy: 222 (56%) were de novo diagnoses and 117 (30%) progressions from non-muscle-invasive disease. After stratification by CrCl (< 40, 40-60, and ≥ 60 ml/min), patients with lower renal function showed older age (76.8, 77.0, and 69.1 years), worse comorbidity profile (CCI: 1.5, 0.7, and 0.6), and markedly higher mortality rates (95.0%, 92.9%, and 42.3%). One hundred ninety-five patients (49.5%) underwent surgery-only, 199 (50.5%) received chemotherapy: 47 (12%) as neoadjuvant, 132 (33.5%) as adjuvant, and 20 (5%) as perioperative treatment. Median DFS was 0.9 years with a time to progression of 2.1 years; median OS was 2.1 years with a 5-year OS rate of 43%.

Conclusions: From this real-world analysis, Italian patients with MIBC emerged as a population of elderly subjects (> 75 years) burdened by comorbidities. Treatment choice was influenced by other factors rather than cisplatin eligibility since only 11% of patients with CrCl ≥ 60 ml/min in 2018 and 20% in 2022 were treated before cystectomy, highlighting a scenario of low adherence to guidelines with underutilization of neoadjuvant chemotherapy.

Introduction: Talquetamab, a bispecific antibody targeting GPRC5D, is approved for triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM) based on results from MonumenTAL-1. We report updated indirect comparisons of talquetamab vs. real-world physician's choice of treatment (RWPC) in patients with TCE RRMM.

Methods: External control arms were created for three MonumenTAL-1 cohorts, two without prior T cell redirection (TCR) therapies who received subcutaneously administered talquetamab 0.4 mg/kg weekly (QW; n = 143) or 0.8 mg/kg every other week (Q2W; n = 154) and one with prior B cell maturation antigen (BCMA) TCR (n = 75) who received either schedule (median follow-up [mFU] 38.2, 31.2, and 30.3 months, respectively), from two real-world studies, LocoMMotion (mFU 26.4 months) and MoMMent (mFU 27.1 months). Imbalances in baseline covariates were adjusted using inverse probability weighting and multivariable regression. The relative effectiveness of talquetamab vs. RWPC was estimated for overall response rate (ORR), ≥ very good partial response (VGPR) rate, and ≥ complete response (CR) rate; odds ratios and relative response ratios (RRs) were derived from weighted logistic regression. Hazard ratios (HRs) for duration of response (DOR), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS) were estimated using a weighted Cox proportional-hazards model.

Results: In the TCR-naïve cohort, talquetamab Q2W had significantly improved outcomes vs. RWPC; RRs were ORR, 2.58; ≥ VGPR, 5.01; ≥ CR, 52.22 and HRs were DOR, 0.52 (p = 0.0011); PFS, 0.47; TTNT, 0.46; OS, 0.35 (all p < 0.0001). Results were similar in the QW cohort. The prior TCR cohort had favorable outcomes with talquetamab vs. RWPC; RRs were ORR, 3.03; ≥ VGPR, 4.88 and HRs were DOR, 0.09, (p = 0.0004); PFS, 0.30 (p < 0.0001); TTNT, 0.26 (p < 0.0001) and OS, 0.37 (p = 0.0020).

Conclusion: With longer follow-up, these comparative analyses further demonstrate the clinical benefit of talquetamab over RWPC in patients with TCE RRMM, irrespective of prior TCR therapy.

Trial registration: MonumenTAL‑1, ClinicalTrials.gov identifier NCT03399799/NCT04634552; LocoMMotion, ClinicalTrials.gov identifier NCT04035226; MoMMent, ClinicalTrials.gov identifier NCT05160584.

Introduction: Fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) is approved for the treatment of asthma in Japan. Currently, data on the safety, particularly on cardiovascular (CV) risk, and effectiveness of FF/UMEC/VI in Japanese real-world clinical practice are limited.

Methods: This prospective, multicenter, post-marketing surveillance was undertaken to assess the safety and effectiveness of once-daily single-inhaler triple therapy FF/UMEC/VI (100/62.5/25 or 200/62.5/25 mcg) newly initiated in patients with asthma in Japan between July 2021 and November 2023. The observation period was 1 year after the first FF/UMEC/VI prescription or until termination or withdrawal from treatment. Safety was assessed by incidence of adverse drug reactions (ADRs) including CV events as safety specification to be checked due to risk associated with use of UMEC. Overall assessment of effectiveness (based on lung function, asthma symptoms, and proportion of patients with exacerbation events) and asthma management status was assessed by the investigator.

Results: Overall, 8.4% (24/286) of patients reported an ADR. The most common ADRs were cough and dysphonia (each 7/286). Urinary retention was reported as a serious ADR in 1 patient, and CV event palpitations were reported in 2 patients. FF/UMEC/VI treatment was deemed effective in 92.5% (260/281) of patients in the effectiveness analysis. Lung function and asthma control test results improved following initiation of FF/UMEC/VI. In the 1 year after initiation, 6.2% (11/178) of patients experienced exacerbation events, while 25.8% (46/178) of patients experienced exacerbation events prior to initiation.

Conclusion: FF/UMEC/VI was well tolerated and effective in the treatment of patients with asthma in Japan. ADRs were reported in 8.4% of patients and the incidence of CV events was low. No new safety concerns were identified.

Introduction: Mirikizumab, an anti-interleukin-23 p19 monoclonal antibody, is approved for treating adults with moderately to severely active ulcerative colitis and Crohn's disease. For ulcerative colitis maintenance therapy, mirikizumab is administered via two 1-ml subcutaneous (SC) injections. Volume and number of SC administrations can impact injection site reactions and local pain, as well as treatment compliance. We assessed the pharmacokinetic (PK) and safety comparability of an investigational one 2-ml SC injection compared with the commercially available two 1-ml SC injections.

Methods: In this phase 1 study, USA-based healthy adults were stratified by weight and randomized (1:1) to receive citrate-free 200 mg SC mirikizumab as either two 1-ml injections (each 100 mg) or one 2-ml (200 mg) injection, delivered by an autoinjector. Participants in each arm were subrandomized by injection site location (arm, abdomen, or thigh). Blood sampling and safety assessments were conducted up to 10 weeks post dose. The primary endpoint was PK, and the secondary endpoint was safety.

Results: A total of 244 participants received one injection and 240 received two injections (mean age 42.5 years; 51.0% female). Baseline characteristics were similar in both groups. Primary PK parameters fell within the bioequivalence range (geometric least-squares mean [GLSM] ratio 0.800-1.250). Observed GLSMs were consistent across injection site locations. Treatment-emergent adverse events were reported in 48 participants with one injection (19.7%) and 55 with two injections (22.9%); most were mild (62/74 events with one injection [83.8%] and 85/100 with two injections [85.0%]). No serious adverse events were reported in either group.

Conclusion: Mirikizumab 200 mg administered as one 2-ml SC injection was bioequivalent to two 1-ml injections, and most treatment-emergent adverse events were mild in both groups. In clinical practice, reducing the number of injections may improve treatment adherence.

Trial registration: ClinicalTrials.gov identifier NCT06475729.

Introduction: Achondroplasia is the most common skeletal dysplasia condition, characterized by disproportionate short stature and delayed motor development. Additional potential complications include bowed legs and hypotonia, otitis media, sleep apnea, and complications from spinal stenosis, which may impose potential burden on individuals with achondroplasia, as well as their families. No reliable, validated, and publicly available achondroplasia-specific clinical outcome assessment (COA) is currently available that can capture the experiences of children and adolescents with achondroplasia. We sought to determine whether existing COA measures have adequate concept coverage for use in clinical studies and understand the challenges for children/adolescents with achondroplasia and their parents through concept elicitation and cognitive debriefing interviews.

Methods: Children/adolescents with achondroplasia and parents of children with achondroplasia participated in combined concept elicitation and cognitive debriefing interviews. Issues raised by participants were mapped to four COA measures to evaluate their clarity, relevance, and appropriateness for use in achondroplasia studies.

Results: Eight children/adolescents (aged 11-16) and 18 parents were interviewed. The challenges most often reported by children/adolescents were feeling hot/sweaty (88%), pain (88%), balance issues or falls (75%), fatigue (63%), muscle fatigue/loose joints (63%), and speech issues (63%). Pain (83%), ear infections (78%), and feeling hot/sweaty (78%) were frequently reported by parents. Difficulty reaching things (88%), running (88%), and walking (75%) were the functional challenges most reported by children/adolescents, while parents most commonly reported difficulty reaching things (78%), toileting (63%), bathing (56%), walking (56%), running (56%), and dressing (50%). Results of response mapping indicated that the QoLISSY, PedsQL, WeeFIM, and Pain-NRS cover most of the important concepts mentioned by parents and children/adolescents.

Conclusions: The PedsQL, QoLISSY, Pain-NRS, and WeeFIM are content valid, appropriate, and relevant to include in future studies of individuals with achondroplasia.