Advances in Therapy最新文献

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a profound global impact. The emergence of several variants during the pandemic has presented numerous challenges in preventing and managing this disease. The development of vaccines has played a pivotal role in controlling the pandemic, with a significant portion of the global population being vaccinated. This, along with the emergence of less virulent SARS-CoV-2 variants, has led to a reduction in the severity of COVID-19 outcomes for the overall population. Nevertheless, individuals with immunocompromising conditions continue to face challenges given their suboptimal response to vaccination and vulnerability to severe COVID-19. This expert review synthesizes recent published evidence regarding the economic and human impact of COVID-19 on such individuals. The literature suggests that rates of hospitalization, intensive care unit admission, and mechanical ventilation use were high during the pre-Omicron era, and remained high during Omicron and later, despite vaccination for this population. Moreover, studies indicated that these individuals experienced a negative impact on their mental health and health-related quality of life (HRQoL) compared to those without immunocompromising conditions, with elevated levels of anxiety, depression, and distress reported. Further, these individuals with immunocompromising conditions experienced substantial costs associated with COVID-19 and loss of income during the pandemic, though the evidence on the economic burden of COVID-19 in such individuals is limited. Generally, COVID-19 has increased healthcare resource use and costs, impaired mental health, and reduced HRQoL in those with varied immunocompromising conditions compared to both those without COVID-19 and the general population—underscoring the importance of continued real-world studies. Ongoing research is crucial to assess the ongoing burden of COVID-19 in vaccinated individuals with immunocompromising conditions who are still at risk of severe COVID-19 outcomes to ensure their needs are not disproportionately worse than the general population.

Introduction

Individuals living with sickle cell disease (SCD) commonly report impaired health-related quality of life (HRQoL). However, impacts of SCD on HRQoL and the unmet needs of SCD treatment/management are under-researched. This study characterized the impact of SCD on HRQoL and identified the unmet needs of individuals with SCD.

Methods

Adults with SCD (aged ≥ 18 years) and caregivers of adolescents (aged 12‒17) with SCD in the United States (US) and United Kingdom (UK) participated in one-on-one virtual semi-structured interviews and focus group discussions (hereafter referred to as ‘interviews’). Interviews were transcribed and thematically analyzed.

Results

Nineteen individuals participated in the study (across five interviews and three focus group discussions), including 18 adults with SCD (United States, n = 11; United Kingdom, n = 7) and one caregiver of an adolescent with SCD (United States). Most participants were female (n = 15). Participants reported negative impacts of SCD on their HRQoL, including the burden of structuring their lives around SCD, due to unpredictable symptoms. They reported negative impacts to psychological health (e.g., depression/low mood and anxiety) and physical health (e.g., chronic pain and fatigue) that affected their social and family life, work, and education, leading to feelings of isolation. Participants expressed concerns about the future, feelings of resentment, and the need for high resilience when facing the barriers/impacts associated with SCD. Many participants reported negative interactions with healthcare professionals, leading to trauma, anxiety, and routine care avoidance. Most participants reported perceived prejudice during routine SCD treatment/management, including being treated as drug-seekers.

Conclusion

Individuals with SCD experience negative HRQoL impacts, including impacts to daily activities, social and family life, work and education, psychological health, and prejudice/stigma. Our findings highlight significant unmet needs of individuals living with SCD, including alternative treatment options to reduce vaso-occlusive crisis (VOC) frequency and treat fatigue.

Introduction

This study compared the relative efficacy of first-line lenvatinib, a standard-of-care treatment for unresectable hepatocellular carcinoma (uHCC), vs licensed/license in-progress comparators. Using inverse probability of treatment weighting (IPTW) and network meta-analysis (NMA), updated evidence for lenvatinib monotherapy from LEAP-002, in addition to evidence from REFLECT, was included in the analyses.

Methods

Randomized controlled trials (RCTs) were identified via systematic review. REFLECT and LEAP-002 investigated lenvatinib in uHCC, with patient-level data available for each; however, only REFLECT included a comparator arm of interest (sorafenib). The lenvatinib arm from LEAP-002 was adjusted to match aggregate data for confounding factors from REFLECT using IPTW. Weighted Cox regressions, including matching variables as covariates, were used to derive hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS). These HR estimates were included in Bayesian NMAs to compare lenvatinib with comparators; survival was significantly improved if the 95% credible interval for the HR did not include 1.0. Scenario analyses explored alternative choices for IPTW estimators.

Results

Eight RCTs (including REFLECT) and the single-arm adjusted lenvatinib data from LEAP-002 were included in the NMA base case. Lenvatinib demonstrated significant improvement in OS compared with sorafenib 400 mg twice daily (BID) and significant improvement in PFS compared with sorafenib 400 mg BID, tremelimumab 300 mg plus durvalumab 1500 mg every 4 weeks (Q4W), and durvalumab 1500 mg Q4W.

Conclusions

These results suggest that patients with uHCC treated with lenvatinib have similar or significantly improved OS and PFS compared with licensed/license in-progress therapies.

Introduction

Patients with uncontrolled, moderate-to-severe asthma have a higher risk for exacerbations, negatively impacting lung function and quality of life. Dupilumab, a fully human monoclonal antibody, blocks interleukins 4 and 13, key and central drivers of type 2 inflammation. Dupilumab has been effective in the treatment of certain types of moderate-to-severe asthma across several clinical trials. We describe the characteristics of patients enrolled in RAPID, a global prospective registry, who initiated dupilumab (primary indication: asthma) in a real-world clinical setting.

Methods

A total of 205 patients (aged ≥ 12 years) were enrolled between March 2020 and October 2021 and are included in this analysis. Data are shown as mean (SD) unless stated otherwise.

Results

Patients were aged 50.1 (17.4) years and were mostly female (65.4%) and white (74.1%). At enrollment, 24.4% reported being current/former smokers and 86.8% had moderate-to-severe asthma (Global Initiative for Asthma steps 3–5). A mean (SD) of 4.4 (6.4) severe asthma exacerbations were reported in the year before enrolling in the registry in 78 of 152 patients with available data. Patients had reduced lung function [pre-bronchodilator forced expiratory volume in 1 s (FEV₁): 2.3 (1.1) L; pre-bronchodilator percent predicted FEV₁: 70.3 (20.3) %] and poor asthma control [6-item Asthma Control Questionnaire: 2.4 (1.2); Asthma Quality of Life Questionnaire: 4.1 (1.3)]. The median (Q1–Q3) blood eosinophil count was 305 (200–695) cells/µL and the mean (SD) fractional exhaled nitric oxide levels were 42 (35) ppb (range: 4–186 ppb).

Conclusion

Our findings suggest that most patients who enrolled in RAPID and initiated dupilumab in real-world clinical settings had a high disease burden, despite receiving current standard-of-care treatment at enrollment.

Acute coronary syndrome (ACS) is a leading cause of death worldwide. Prompt and accurate diagnosis of acute myocardial infarction (AMI) or ACS is crucial for improved management and prognosis of patients. The rapid growth of machine learning (ML) research has significantly enhanced our understanding of ACS. Most studies have focused on applying ML to detect ACS, predict prognosis, manage treatment, identify risk factors, and discover potential biomarkers, particularly using data from electrocardiograms (ECGs), electronic medical records (EMRs), imaging, and omics as the main data modality. Additionally, integrating ML with smart devices such as wearables, smartphones, and sensor technology enables real-time dynamic assessments, enhancing clinical care for patients with ACS. This review provided an overview of the workflow and key concepts of ML as they relate to ACS. It then provides an overview of current ML algorithms used for ACS diagnosis, prognosis, identification of potential risk biomarkers, and management. Furthermore, we discuss the current challenges faced by ML algorithms in this field and how they might be addressed in the future, especially in the context of medicine.

Introduction

To investigate outcomes in adults with type 2 diabetes who switched to once-weekly (OW) semaglutide from another glucagon-like peptide-1 receptor agonist (GLP-1RA) in clinical practice.

Methods

This post hoc analysis used data from the SemaglUtide Real-world Evidence (SURE) program, which included nine observational studies investigating the initiation of OW semaglutide in people with type 2 diabetes in routine clinical practice. Using a random coefficient-adjusted mixed model for repeated measurements, changes in glycosylated hemoglobin (HbA_1c), body weight, and body mass index were analyzed for GLP-1RA-experienced patients who had at least one documented HbA_1c value within the 12 weeks before switching to OW semaglutide. In addition, descriptive statistics were used for HbA_1c, body weight target achievement, and safety data.

Results

Of the 3,505 patients included in the nine SURE studies, 651 switched to OW semaglutide from another GLP-1RA. GLP-1RA-experienced patients who switched to OW semaglutide demonstrated a 0.67%-point [95% confidence interval (CI) − 0.74; − 0.60, p < 0.0001] reduction in HbA_1c, and a 3.69-kg [95% CI − 3.98; − 3.41, p < 0.0001] reduction in body weight over 30 weeks. A body weight reduction of ≥ 5% was achieved by 27.6% of patients, and 33.3% of patients with baseline HbA_1c ≥ 7% achieved HbA_1c < 7% at end of study. No new safety concerns were identified.

Conclusions

Data from this post hoc analysis suggest that, for those not adequately responding to treatment with other GLP-1RAs, switching to OW semaglutide could provide additional glycemic and weight benefits with the convenience of an OW dosing regimen.

Graphical abstract

A graphical abstract is available with this article.

Introduction

This analysis evaluated literature on patients with activated phosphoinositide 3-kinase delta syndrome (APDS) to better understand the genetic etiologies and occurrence of mortality in this population.

Methods

A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses approach, including all articles published in English prior to March 13, 2023, in PubMed and Embase. Patients included in the study had reported either (1) APDS diagnosis or (2) ≥ 1 clinical sign consistent with APDS and a first-degree relative with genetically confirmed APDS. Reported age at last observation was also a required outcome. Publications not meeting these criteria were excluded. Data were summarized using descriptive statistics.

Results

The search identified 108 publications describing 351 unique patients with 39 distinct disease-causing variants. Among these, 41 (12%) deaths were reported, with a mean age at last follow-up of 19.6 (range, 1–64) years. A cause of death was reported for 80% (33/41) of deaths; lymphoma (24%, 10/41) and infections (22%, 9/41) were the most common causes. Types of infections causing death were severe uncontrollable infections (n = 3), sepsis (n = 2), viral infection (varicella zoster pneumonitis [n = 1], cytomegalovirus and adenovirus [n = 1], and Epstein-Barr virus [n = 1]), and infection (n = 1). Mean age at death for lymphoma was 24.9 (range, 1–41) years, and all nine patients who died from infections died before the age of 15 years. The mean age at first APDS symptom was 2.0 (range, < 1–22) years, and mean age at APDS diagnosis was 13.4 (range, 0–56) years; the mean time between symptoms and diagnosis was 10.6 (range, 0–44) years. Limitations of the study were primarily related to the data source.

Conclusion

Patients with APDS suffer early mortality, largely from lymphoma and infection, with large time gaps between symptoms and diagnosis. These findings highlight the need for improved diagnostics, earlier genetic testing for APDS, increased awareness of familial testing, and targeted therapies.

Introduction

Obexelimab is an investigational, bifunctional, non-depleting, humanized monoclonal antibody that binds CD19 and FcγRIIb to inhibit B cells, plasmablasts, and CD19-expressing plasma cells. In clinical trials, intravenous (IV) administration of obexelimab has been well-tolerated, and demonstrated clinical activity in patients with rheumatoid arthritis, systemic lupus erythematosus, and immunoglobulin G4-related disease. This study was performed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of obexelimab following subcutaneous (SC) administration, and compare PK/PD profiles between healthy Japanese and non-Japanese volunteers.

Methods

This was a Phase I, open-label, parallel group, multiple-dose study. Participants were randomized to five cohorts to receive three doses of obexelimab as 125 mg SC every 14 days (q14d), 250 mg SC q14d, 375 mg SC q14d, 250 mg IV q14d, and 125 mg SC every 7 days, then monitored during a 28-day safety follow-up period. PK/PD assessments were performed after the first and third doses.

Results

A total of 50 healthy volunteers (25 Japanese and 25 non-Japanese) were enrolled and distributed evenly between dose cohorts. All SC dosing regimens were well-tolerated. Dose-proportional PK was observed following SC doses with a bioavailability of approximately 60%. No clinically meaningful differences in PK parameters were found between healthy Japanese and non-Japanese participants. Antidrug antibodies (ADA) were detected in 6/50 (12%) participants after dosing. ADA had no or minimal impact on PK in all six ADA positive participants. Near-complete CD19 receptor occupancy and an absolute B-cell count nadir of approximately 50% baseline levels were maintained for the duration of the study in both populations.

Conclusion

Obexelimab SC administration demonstrated favorable bioavailability, was well-tolerated, and showed no clinically meaningful ethnic differences in PK/PD. These results support further clinical development of SC obexelimab to treat B-cell mediated autoimmune diseases.

Trial Registration

NCT02867098.

Introduction

Previously, adherence and persistence to treatment have been shown to improve outcomes among patients with chronic obstructive pulmonary disease (COPD). This study aimed to evaluate adherence and persistence to single-inhaler triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI; one inhalation, once-daily) compared with budesonide/glycopyrrolate/formoterol fumarate (BUD/GLY/FOR; two inhalations, twice-daily) among patients with COPD in the USA.

Methods

This retrospective weighted cohort study used claims data from the IQVIA PharMetrics^® Plus Database from October 1, 2019 to March 31, 2023, to identify patients with COPD newly initiating FF/UMEC/VI or BUD/GLY/FOR. Index date was the first pharmacy claim for FF/UMEC/VI or BUD/GLY/FOR on or after October 1, 2020. The longest follow-up period was 12 months. Inverse probability of treatment weighting was used to balance baseline characteristics between cohorts. Adherence was measured as mean proportion of days covered (PDC); the proportion of patients with PDC ≥ 0.5 and PDC ≥ 0.8 was also assessed. Persistence was assessed as time to treatment discontinuation using Kaplan–Meier rates.

Results

Overall, 8912 and 2685 patients were included in the FF/UMEC/VI and BUD/GLY/FOR cohorts, respectively. After weighting, mean age and proportion of patients with Medicare Advantage insurance was 64.62 years and 40.0% in the FF/UMEC/VI cohort and 63.96 years and 36.1% in the BUD/GLY/FOR cohort. At 6 months post-index, mean PDC was greater in the FF/UMEC/VI versus the BUD/GLY/FOR cohort (0.65 versus 0.59; P < 0.001). A significantly greater proportion of patients in the FF/UMEC/VI versus the BUD/GLY/FOR cohort had PDC ≥ 0.8 (45.6% versus 34.5%; P < 0.001) and PDC ≥ 0.5 (71.8% versus 64.3%; P < 0.001). Results were consistent at 12 months post-index. When a 30-day gap was used to define treatment discontinuation, the FF/UMEC/VI cohort had statistically significantly greater treatment persistence versus the BUD/GLY/FOR cohort at all time points.

Conclusion

In this study, patients initiating FF/UMEC/VI had significantly greater adherence and persistence to treatment than patients initiating BUD/GLY/FOR.

Introduction

A slower adoption rate of fixed dose combinations (FDC) in diabetes management is partly due to insufficient data. This study evaluates the safety and efficacy of an FDC of dapagliflozin + sitagliptin + metformin hydrochloride extended release (XR), compared to a dual FDC of sitagliptin + metformin hydrochloride XR among patients with type 2 diabetes mellitus (T2DM) with poor glycemic control when treated with metformin monotherapy.

Methods

A total of 274 patients with T2DM were randomized (1:1) to either arm X, receiving FDC of dapagliflozin (10 mg) + sitagliptin (100 mg) + metformin hydrochloride XR (1000 mg) (Dapa + Sita + Met) tablets, or arm Y, receiving sitagliptin phosphate (100 mg) + metformin hydrochloride XR (1000 mg) (Sita + Met) tablets, and treated for 16 weeks. The outcome measures included changes in hemoglobin A1c (HbA1c)(%), fasting plasma glucose (FPG), 2-h post-prandial glucose (PPG), weight, and the proportion of patients achieving target HbA1c levels of < 7.0% by week 16 of the study period.

Results

The reduction in HbA1c at week 16 was significantly higher in arm X than in arm Y [estimated treatment difference (ETD), − 0.65% (95% CI − 0.76 to − 0.53; P < 0.0001)]. Arm X showed a marked decrease in FPG [ETD − 15.42 mg/dl; 95% CI (17.63, 13.22; P < 0.0001)], PPG [ETD − 30.39 mg/dl; 95% CI (35.59, 25.19; P < 0.0001)], and weight [ETD − 1.47 kg; 95% CI (1.59, 1.28; P < 0.0001)] after 16 weeks. In arm X, 54% of patients reached HbA1c < 7.0% compared to 29.9% in arm Y. The incidence of adverse events was comparable [13.14% (arm X) vs 12.4% (arm Y)]. There was no severe hypoglycemia-led treatment discontinuation.

Conclusion

Among patients with T2DM who have poor glycemic control with metformin monotherapy, triple FDC (Dapa + Sita + Met) effectively helped achieve better glycemic response compared to dual FDC (Sita + Met), with a comparable safety and tolerability profile.

Trial Registration

CTRI/2022/01/039857