Advances in Therapy最新文献

Introduction: X-linked retinitis pigmentosa (XLRP) is one of the most severe forms of retinitis pigmentosa, representing 5-15% of all cases. There is a notable gap in understanding the health-related quality of life (HRQoL) impact on carers of people with XLRP, essential for holistic health economic evaluations. The objective of the study is to estimate health state utilities of informal carers for a person with XLRP which can be used in economic modelling.

Method: Four carer descriptions or "vignettes" were developed for mild, moderate, severe, and completely blind XLRP patient care. The vignettes were based on studies identified in a targeted literature review and validated through qualitative interviews with informal carers and an ophthalmologist. The vignettes were valued using the time trade-off (TTO) method by the general population of Great Britain. Descriptive statistics of the data were analysed.

Results: A total of 220 respondents completed the survey. The mean utility value for providing care to someone with mild XLRP was 0.85, decreasing to 0.76 when caring for someone with moderate XLRP and further decreasing to 0.54 when caring for someone with severe XLRP. The mean carer utility declined to 0.42 for complete blindness.

Conclusion: Mean carer utility declined with increased severity of patient XLRP with the most substantial decline calculated when moving from moderate to severe XLRP. This is the first study to generate utility values reflecting HRQoL of carers of patients with XLRP, by different levels of disease severity, and finds that carer utility decreases with increased XLRP severity in patients.

Introduction: Delamanid (Deltyba®), a medicinal product with an orphan designation for the treatment of tuberculosis, received a conditional marketing authorisation in the European Union (EU) based on phase 2 data, while phase 3 trial was ongoing. The list of adverse drug reactions (ADRs) in the original Summary of Product Characteristics (SmPC) contained all adverse events (AEs) considered related by the investigator that were reported in at least one of the 321 patients receiving delamanid. The safety profile observed after completion of the phase 3 clinical trial, post-marketing studies and spontaneous reports from post-marketing appeared different from what the initial SmPC was indicating. A comprehensive analysis was undertaken aiming to provide evidence for identification of a well-substantiated and clinically useful delamanid safety profile.

Methods: In support of the process of ADR identification, a statistical methodology of data from controlled clinical trials was introduced based on the estimation of risk difference and risk ratio for identification of a potential risk from delamanid in high and low incidence situations. Final medical assessment was supported by this statistical analysis of data from controlled clinical trials, any signal from all other Otsuka-sponsored clinical trials, along with data from post-marketing solicited and unsolicited sources.

Results: ADRs were either retained, added to or removed from the ADR list with the same or modified frequency. Thus, the total number of ADRs listed in the original SmPC was significantly reduced.

Conclusion: A combination of statistical parameters and medical judgement should be considered for the selection of undesirable effects for the product label and for the safety risk classification.

Introduction: Oral selexipag is indicated to delay disease progression and reduce risk of pulmonary arterial hypertension (PAH)-related hospitalization, as demonstrated in GRIPHON. There are situations when clinicians or patients may need or want to transition from parenteral, oral, and inhaled prostacyclin pathway agents (PPAs) to oral selexipag. This systematic literature review (SLR) examined published evidence on such transitions in adults.

Methods: A SLR was conducted in Medline and Embase for publications from January 01, 2015 to September 25, 2024. Two reviewers independently screened abstracts and full texts; one extracted relevant data.

Results: Overall, 1730 publications were identified, with 48 included. Of these, 32 transitions from treprostinil and 16 from epoprostenol to oral selexipag were identified. Patient ages ranged from 19 to 78 years, with varying risk status and scores, functional classes, and comorbidities. Reasons for transition were patient-specific, with publications generally following GRIPHON and Food and Drug Administration (FDA) label protocols.

Conclusion: This review highlights cases where oral selexipag may be a suitable option when clinicians and patients participate in shared decision-making considering safety and risks/benefits. Transitions should be individualized based on clinical assessment, with appropriate monitoring and follow-up.

Alpha-1 antitrypsin deficiency (AATD) is a rare, underdiagnosed genetic disorder characterized by deficient or dysfunctional alpha-1 antitrypsin (AAT), leading to unopposed neutrophil protease activity. This can often lead to progressive lung and liver damage, and in rare cases panniculitis, which can be potentially lethal. Current diagnostic strategies rely on a stepwise approach beginning with serum AAT measurement, followed by phenotyping and genotyping to confirm pathogenic variants. Despite recommendations from major respiratory societies to test all patients with chronic obstructive pulmonary disease (COPD), unexplained liver disease, panniculitis, and vasculitis, delayed recognition persists because of clinical overlap with asthma, COPD, and alcohol- and non-alcohol-related liver disease. Management emphasizes lifestyle modification, avoidance of risk factors, and pharmacological support. Currently, intravenous augmentation therapy is the only disease-modifying option approved for pulmonary disease. Augmentation is expensive and variably available, or reimbursed worldwide. Surgical and interventional approaches, including lung volume reduction techniques and transplantation, provide options for advanced disease, although outcomes vary. Emerging therapies, such as inhaled AAT formulations, recombinant fusion proteins, RNA-editing platforms, and DNA editing using CRISPR-based strategies, aim to correct the protease-antiprotease imbalance and restore endogenous AAT production. The therapeutic landscape is rapidly evolving, but significant challenges remain in improving early detection, broadening access to effective treatments, and optimizing individualized care. Future advances will likely depend on integrating newer therapies with early intervention strategies to preserve organ function and improve long-term prognosis.

Introduction: Trofinetide is an approved treatment in the USA and Canada for Rett syndrome in patients aged ≥ 2 years. Trofinetide is currently supplied as a ready-to-use oral solution (TOS). A new trofinetide powder for oral solution (TPOS) offers potential advantages: smaller configuration of unit-dose packs; excludes preservatives, synthetic red dye, and maltitol; can be dissolved in a range of volumes in cold/room temperature water or water-based beverages; does not require refrigeration. To ensure that the formulation change does not impact trofinetide pharmacokinetics, a bioequivalence study assessed trofinetide pharmacokinetics after single 12,000-mg oral trofinetide doses administered as TOS and TPOS and the impact of a reduced constitution volume on trofinetide bioavailability.

Methods: In this randomized, open-label, three-period, three-treatment design study, 38 healthy adults each received one 12,000-mg trofinetide dose of TOS (60 mL [200 mg/mL]; treatment A), TPOS constituted in 60 mL of water (200 mg/mL; treatment B), and TPOS constituted in 25 mL of water (480 mg/mL; treatment C) in sequence ABC or BAC. Bioequivalence for each treatment comparison was confirmed if the 90% confidence interval (CI) of the geometric mean ratio (GMR) for the maximum observed drug concentration (C_max), area under the concentration-time curve from time 0 to time t (AUC_0-t), and AUC from time 0 to infinity (AUC_0-∞) fell within 80-125%.

Results: The criteria for bioequivalence were met for AUC_0-t (GMR 99.62%; CI 96.52-102.83), AUC_0-∞ (GMR 99.50%; CI 96.44-102.66), and C_max (GMR 99.52%; CI 94.99-104.27) between treatment B and treatment A. All other treatment comparisons (C vs A and B vs C) also met the bioequivalence criteria. The most frequent treatment-emergent adverse event was diarrhea (n = 6 [15.8%]). No serious or unexpected adverse events occurred during the study.

Conclusion: The bioequivalence demonstrated in this study supports the clinical interchangeability of TPOS and TOS and shows that TPOS can be constituted using adjustable volumes of water without affecting bioavailability. There were no unexpected adverse events reported with trofinetide when administered as TPOS and TOS.

Introduction: Human epidermal growth factor receptor type 2 (HER2) is overexpressed in 15-20% of primary invasive breast cancers, serving as a key predictive and prognostic factor. HER2-low is defined as immunohistochemistry (IHC) 1+ or 2+ with in situ hybridization (ISH) negative and HER2-ultralow is defined as membrane staining that is incomplete, faint/barely perceptible, and in at most 10% of tumor cells (0+/with membrane staining). Trastuzumab deruxtecan has shown improved outcomes in multiple clinical trials between these groups. A Delphi study was conducted to address challenges in testing, sampling, and reporting, and to identify unmet needs in Asia.

Methods: The study comprised two online surveys and a participant meeting with 15 pathologists from nine countries in Asia and the Indo-Pacific region. Responses were recorded for 57 close-ended and 33 open-ended statements using a 1-9-point Likert scale ranging from agreement to disagreement with a consensus threshold of 75%.

Results: All participants completed both surveys and the meeting (100% response). Consensus was reached on 33/57 closed-ended statements (survey 1, 27/47; survey 2, 6/21), while 24/57 did not reach consensus. Ninety-three percent of participants agreed that biopsies of recurrent lesions should be performed, especially if the primary tumor was HER2-zero. Initially, participants did not reach consensus (73% agreement) on reassessing HER2 results for metastatic lesions scored as HER2-zero but later reached consensus (80% agreement). All testing-related questions reached consensus in survey 1.

Conclusion: This Delphi study found strong consensus on key concepts for sampling, pathological testing, interpretation, and reporting of HER2-low and ultralow breast cancer. While the opinions expressed align with current guidelines, more evidence on the clinicopathological implications is needed.

Introduction: Over the past 2 decades, treatment for type 2 diabetes (T2D) has evolved with the introduction of medications that offer greater simplicity. The Simplicity of Diabetes Treatment Questionnaire (Sim-Q™) was developed to assess the simplicity or complexity of treatment for T2D. This study assessed the psychometric properties of the Sim-Q.

Methods: Eight clinical sites in the USA recruited participants treated for T2D with a variety of medications, including oral medications, insulin, glucagon-like peptide 1 (GLP-1) receptor agonists, and a dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist. Psychometric analysis of the Sim-Q focused on item performance, item selection, exploratory factor analysis (EFA), reliability (internal consistency and test-retest), and validity (construct and known-groups).

Results: The study included 250 participants (mean age 59.7 years; 54.4% female). On the basis of item performance and EFA, eight items were retained for the Simplicity of Diabetes Management Subscale assessing simplicity of treatment attributes. Two global items assessing simplicity of medication for diabetes and simplicity of overall diabetes management were scored separately. The Simplicity of Diabetes Management Subscale had good internal consistency reliability (Cronbach's alpha 0.90). The Simplicity of Diabetes Management Subscale and two global items had acceptable test-retest reliability (intraclass correlation coefficients 0.80, 0.72, and 0.73). Convergent validity was supported by significant correlations (P < 0.0001) with related measures. The Sim-Q distinguished between groups of participants who differed in their satisfaction with the ease and convenience of their treatment. For example, the two global items differentiated between groups receiving different treatments (tirzepatide and injectable semaglutide).

Conclusion: The Sim-Q demonstrated good reliability and validity in this psychometric study. This measure may be useful for assessing individuals' perceptions of treatment simplicity in clinical trials and clinical practice.

Introduction: This study aimed to identify potential concepts of interest (COIs) and clinical outcome assessments (COAs) for late-onset and infantile-onset Pompe disease (LOPD and IOPD) and to assess whether the current COAs are reliable and valid to capture patients' experiences.

Methods: Two literature reviews were conducted to identify, describe, and document key signs, symptoms, and impacts relevant to patients and to identify COAs used in Pompe disease. The COAs identified were mapped against the potential COIs to determine which instruments provided the best concept coverage from a patient perspective. Shortlisted COAs were further examined to assess their content validity and psychometric properties.

Results: Sixteen articles for LOPD and 9 for IOPD were identified for concept extraction. Patients with Pompe disease experience a range of signs, symptoms, and impacts. Most COAs currently used in Pompe disease are generic; only 3 LOPD COAs and 1 IOPD COA were disease-specific. Following mapping, 14 instruments for LOPD and 4 for IOPD were identified as providing the greatest coverage, with notable evidence gaps supporting content validity and/or psychometric properties of all shortlisted COAs.

Conclusion: Several COIs were identified from the literature that may be of importance to patients with Pompe disease. Individual COAs frequently used in assessing these concepts were found to have gaps with regards to content validity and psychometric properties. Additional research with patients with Pompe disease could be considered to address issues of content validity. Furthermore, the use of several COAs could be considered in future studies to capture what matters most to patients with Pompe disease.

Introduction: Generalized myasthenia gravis (gMG) is a rare, chronic autoimmune neuromuscular disorder that currently lacks a curative treatment. Efgartigimod alfa is the first human IgG1 Fc fragment approved in Spain for the management of this condition. This study aims to evaluate the value of efgartigimod for treating gMG with anti-acetylcholine receptor (gMG AChR+) antibodies compared with ravulizumab, zilucoplan, and rozanolixizumab using a multi-criteria decision analysis (MCDA) framework.

Methods: A multidisciplinary group of eight experts evaluated the value of efgartigimod against ravulizumab, zilucoplan, and rozanolixizumab. The MCDA framework adapted for evaluating orphan drugs (ODs) in Spain, comprising nine quantitative and three qualitative criteria, was used.

Results: gMG AChR+ has been recognised as a severe and debilitating condition with considerable unmet needs. Efgartigimod achieved favourable average scores compared with ravulizumab, zilucoplan, and rozanolixizumab across all comparative parameters, including efficacy, safety, and patient-reported outcomes (PROs), potentially resulting in cost savings. Efgartigimod was deemed to have a significant therapeutic impact, with supporting data considered high quality. Efgartigimod alfa showed a higher overall value contribution than the three comparators, with the difference being most notable for ravulizumab. Furthermore, it was concluded that efgartigimod aligns well with the specific priorities, objectives, and capacities of the National Healthcare System (NHS).

Conclusion: Efgartigimod has been recognised as a valuable option for gMG AChR+ treatment in Spain by a multidisciplinary panel of experts through the application of MCDA, receiving higher scores compared with ravulizumab, zilucoplan, and rozanolixizumab.