Advances in Therapy最新文献

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

Objectives

Fabry disease (FD) is a rare metabolic disorder which presents with considerable heterogeneity in disease characteristics. Given the absence of interventional studies comparing all available treatments, it is important for indirect treatment comparisons (ITCs) to account for potential treatment effect modifiers (TEMs). This systematic literature review (SLR) aimed to identify patient characteristics that may impact clinical outcomes by analyzing real-world evidence (RWE) in FD.

Methods

An SLR was conducted according to PRISMA guidelines, with searches performed in the EMBASE, MEDLINE, and Cochrane databases (1946–2022; with a recent update in April 2023). Full-text articles reporting clinical outcomes from RWE studies of pharmacological therapies for the treatment of FD were included.

Results

Including studies from the recent SLR update, a total of 119 original studies met the PICOS criteria and 25 studies provided insights into TEMS. Potential TEMs in FD were identified: sex, age, timing of treatment initiation (early/delayed), left ventricular hypertrophy (LVH), estimated glomerular filtration rate (eGFR), proteinuria, presence of anti-drug-antibodies (ADAs) at baseline, and previous enzyme replacement therapy (ERT). In three studies (two including ERT-treated patients and one study of migalastat-treated patients) males showed worse renal outcomes than females. Five studies found that younger patients and those who received initial ERT before the age of 25 years had greater reductions in plasma-lysoGb3, as well as more favorable renal, cardiac, and biochemical outcomes. Seven studies identified associations between LVH and reduced eGFR at baseline, along with an increased risk of cardiovascular, renal, and neurological events. In four studies, lower baseline eGFR and proteinuria were associated with faster annual eGFR decline despite ERT; high baseline proteinuria was a significant predictor of renal disease progression. Baseline ADAs were linked to lower eGFR, increased left ventricular mass, and reduced treatment impact on plasma/urine-lysoGb3. Migalastat was effective in treatment-naïve patients, while those previously treated with ERT experienced deteriorations in mean lysoGb3, eGFR, and left ventricular mass.

Conclusions

This SLR highlighted several patient characteristics that influence treatment effectiveness in FD. It is important to account for these characteristics in ITCs to ensure unbiased outcomes.

Introduction

Vaccines can prevent influenza (flu) infections and are cost-effective for society and healthcare. However, the cost-effectiveness of post-exposure prophylaxis as a follow-up strategy is unclear. This study aims to evaluate the cost utility of post-exposure prophylaxis and treatment strategies with neuraminidase inhibitors and a cap-dependent endonuclease inhibitor for flu infections from the perspective of healthcare costs in Japan.

Methods

A base-case analysis was used to compare oseltamivir, zanamivir, and laninamivir for neuraminidase inhibitors and baloxavir marboxil for the endonuclease inhibitor. The costs of the first visit to a physician and pharmacy were excluded because of the policy on out-of-pocket expenses for post-exposure prophylaxis in Japan. Direct medical costs include the second physician visit, pharmacy and hospital admission expenses, and drug prices, based on the 2020 Japanese Medical Fee Index. The EuroQol-5Dimention-5Level was utilized to measure healthy participants’ quality of life scores, with a time horizon of 14 days. Deterministic and probabilistic sensitivity analyses were conducted.

Results

We have found baloxavir marboxil as the post-exposure prophylaxis agent and laninamivir as the treatment agent to be the most cost-effective strategy in Japan, followed by oseltamivir as the post-exposure prophylaxis agent and zanamivir as the treatment agent.

Conclusions

Baloxavir marboxil and oseltamivir are cost-effective prophylactic agents for flu from the perspective of healthcare costs in Japan. This strategy to select baloxavir marboxil or oseltamivir would be helpful to manage a formulary for post-exposure prophylaxis in Japan.

Fabry disease (FD) is a rare lysosomal storage disorder that is characterized by renal, neurological, and cardiovascular dysfunction. Four treatments are currently available for patients with FD; three enzyme replacement therapies (ERTs; agalsidase alfa, agalsidase beta, and pegunigalsidase alfa) and one pharmacological chaperone (migalastat). This review focuses on the evidence for the benefits of ERTs and migalastat, and provides an overview of their impact on disease manifestations and quality of life (QoL). Agalsidase beta is associated with renal, neurological, and cardiovascular benefits, and may prevent renal disease progression. Agalsidase alfa provides stabilizing effects across all main organ systems, although minor sex-specific differences exist in patients with more advanced baseline disease. The benefits of agalsidase alfa and agalsidase beta are similar but depend on the extent of baseline disease. Some data indicate that agalsidase beta may be preferable over the longer term. Both agalsidase alfa and agalsidase beta are associated with improved gastrointestinal and pain symptoms, as well as improved QoL. Patients with advanced end-organ damage tend not to respond as optimally to ERTs as those who initiate ERTs before irreversible organ fibrosis develops, highlighting the need for early treatment initiation. Migalastat, which is only approved for patients with amenable missense gene variants, generally stabilizes renal parameters and provides cardiovascular benefits. Migalastat also improves diarrhea and pain, and stabilizes QoL (although ERT may be more effective for pain management), but the neurological effects of migalastat have not been studied. Real-world data raise concerns about effective in vivo amenability of some genetic variants. Future studies with direct treatment comparisons in patients with FD are needed.