BioDrugs最新文献

Two monoclonal antibodies (mAbs), aducanumab and lecanemab, have received accelerated approval from the US FDA for initiation of treatment in early Alzheimer's disease patients who have proven β-amyloid pathology (Aβ). One of these, lecanemab, has subsequently received full approval and other monoclonal antibodies are poised for positive review and approval. Anti-amyloid mAbs share the feature of producing a marked reduction in total brain Aβ revealed by amyloid positron emission tomography. Trials associated with slowing of cognitive decline have achieved a reduction in measurable plaque Aβ in the range of 15-25 centiloids; trials of agents that did not reach this threshold were not associated with cognitive benefit. mAbs have differences in terms of titration schedules, MRI monitoring schedules for amyloid-related imaging abnormalities (ARIA), and continuing versus interrupted therapy. The approximate 30% slowing of decline observed with mAbs is clinically meaningful in terms of extended cognitive integrity and delay of onset of the more severe dementia phases of Alzheimer's disease. Approval of these agents initiates a new era in Alzheimer's disease therapeutics with disease-modifying properties. Further advances are needed, i.e. greater efficacy, improved safety, enhanced convenience, and better understanding of ill-understood observations such as brain volume loss.

Objective

The aim was to assess the influence of the presence of biosimilar adalimumab on adalimumab budget savings in 14 high- and upper-middle-income countries.

Methods

This study analyzed Multinational Integrated Data Analysis System (MIDAS)-IQVIA data from the fourth quarter (Q4) of 2018 to the Q4 of 2019, comparing adalimumab expenditure (in United States dollars) and consumption (in standard units [SU]) across 14 countries (Australia, Austria, Brazil, Canada, France, Germany, Italy, Japan, Korea, Singapore, South Africa, Spain, Sweden, and Taiwan). The countries were divided into two groups based on the availability of adalimumab biosimilars during the study period. A difference-in-difference design was employed to analyze the groups, focusing on changes from Q4 2018 to Q4 2019. Additionally, changes in adalimumab expenditure were decomposed into price, quantity, and drug mix during the study period.

Results

Among countries with adalimumab biosimilars, there was a significant decrease in expenditure (− $371.0 per gross domestic product per capita; p = 0.03) over four quarters, while the consumption significantly increased (1.0 SU per 1000 population; p = 0.02). This was consistent with visual observations and differed from countries without adalimumab biosimilar. Sensitivity analysis with a narrowed list of countries (12 high-income countries) showed a consistent trend. Adalimumab expenditure decreased by 14% during the study period in countries where adalimumab biosimilars were available, mainly due to the price changes (P_t = 0.85; − 15%) and the drug-mix effect (ε_t = 0.88; − 12%). Yet, adalimumab expenditure (E_t = 1.04; +4%) changed in a quantity-dependent manner (Q_t = 1.06; +6%) in countries where adalimumab biosimilars were absent.

Conclusion

The availability of biosimilars was associated with a decrease in adalimumab expenditure without compromising the consumption of adalimumab.

Immune checkpoint blockade (ICB) has improved outcomes for patients with advanced non-small cell lung carcinoma (NSCLC). Building off of this, it has been hypothesized that the utilization of ICB early during the disease course may be advantageous, particularly in the neoadjuvant setting prior to definitive surgical resection. Preclinical studies have suggested that a more potent immune response may be induced by neoadjuvant ICB in the presence of a higher antigen burden and intact tumor draining lymph nodes. Recent clinical trials evaluating neoadjuvant ICB with or without chemotherapy combinations in patients with resectable NSCLC led to improved pathological responses and longer event-free survival when neoadjuvant ICB was added to chemotherapy. Surgical outcomes were also supportive of this approach, with encouraging rates of pathological downstaging. Additionally, the availability of pre-treatment biopsy samples and post-treatment surgical resection tissues facilitates the conducting of correlative studies that continue to improve our understanding of the mechanisms of response and resistance to ICB. As long-term survival outcomes from ongoing clinical trials are awaited, several important questions require further investigation, including the optimal duration of neoadjuvant therapy, the clinical endpoints most predictive of long-term outcomes, and translational studies that should be investigated in future trial designs. Additionally, the optimal clinical management of patients with residual disease at the time of surgical resection and those who experience recurrence remains to be determined. In this review, we will (1) discuss the rationale behind neoadjuvant ICB-based therapy in NSCLC, (2) summarize the clinical data available thus far, and (3) highlight unanswered questions that need to be addressed in future studies to maximize the clinical benefits of this approach.

Clostridioides difficile is one of the most important causes of healthcare-associated diarrhea. The high incidence and recurrence rates of C. difficile infection, as well as its associated morbidity and mortality, are great concerns. The most common complication of C. difficile infection is recurrence, with rates of 20-30% after a primary infection and 60% after three or more episodes. Medical management of recurrent C. difficile infection involves a choice of therapy that is different from the antibiotic used in the primary episode. Patients with recurrent C. difficile infection also benefit from fecal microbiota transplantation or standardized microbiome restoration therapies (approved or experimental) to restore eubiosis. In contrast to antibiotics, microbiome restoration therapies restore a normal gut flora and eliminate C. difficile colonization and infection. Fecal microbiota transplantation in recurrent C. difficile infection has demonstrated higher success rates than vancomycin, fidaxomicin, or placebo. Fecal microbiota transplantation has traditionally been considered safe, with the most common adverse reactions being abdominal discomfort, and diarrhea, and rare serious adverse events. Significant heterogeneity and a lack of standardization regarding the process of preparation, and administration of fecal microbiota transplantation remain a major pitfall. Standardized microbiome-based therapies provide a promising alternative. In the ECOSPOR III trial of SER-109, an oral formulation of bacterial spores, a significant reduction in the recurrence rate (12%) was observed compared with placebo (40%). In the phase III PUNCH CD3 trial, RBX2660 also demonstrated high efficacy rates of 70.6% versus 57.5%. Both these agents are now US Food and Drug Administration approved for recurrent C. difficile infection. Other standardized microbiome-based therapies currently in the pipeline are VE303, RBX7455, and MET-2. Antibiotic neutralization strategies, vaccines, passive monoclonal antibodies, and drug repurposing are other therapeutic strategies being explored to treat C. difficile infection.

Over the past few years, there has been a surge in the industrial production of recombinant enzymes from microorganisms due to their catalytic characteristics being highly efficient, selective, and biocompatible. L-asparaginase (L-ASNase) is an enzyme belonging to the class of amidohydrolases that catalyzes the hydrolysis of L-asparagine into L-aspartic acid and ammonia. It has been widely investigated as a biologic agent for its antineoplastic properties in treating acute lymphoblastic leukemia. The demand for L-ASNase is mainly met by the production of recombinant type II L-ASNase from Escherichia coli and Erwinia chrysanthemi. However, the presence of immunogenic proteins in L-ASNase sourced from prokaryotes has been known to result in adverse reactions in patients undergoing treatment. As a result, efforts are being made to explore strategies that can help mitigate the immunogenicity of the drug. This review gives an overview of recent biotechnological breakthroughs in enzyme engineering techniques and technologies used to improve anti-leukemic L-ASNase, taking into account the pharmacological importance of L-ASNase.

Background and objective: Behçet's disease (BD) is a variable vessel vasculitis. Biologic drugs are increasingly used in the treatment of BD. We aimed to analyze biologic drug use in the treatment of pediatric BD.

Methods: MEDLINE/PubMed and Scopus databases were searched from the inception of these databases until 15 November 2022, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Only reports presenting data of pediatric patients with BD (BD diagnosis < 18 years of age) treated with biologic drugs were included. The demographic features, clinical characteristics, and data on treatment were extracted from the included papers.

Results: We included 87 articles including 187 pediatric patients with BD treated with biologic drugs (215 biologic treatments). Tumor necrosis factor (TNF)-α inhibitors (176 treatments) were the most frequently used biologic drugs followed by interferons (21 treatments). Other reported biologic treatments were anti-interleukin-1 agents (n = 11), tocilizumab (n = 4), daclizumab (n = 2), and rituximab (n = 1). The most common indication for biologic drug use was ocular involvement (93 treatments) followed by multisystem active disease (29 treatments). Monoclonal TNF-α inhibitors, adalimumab and infliximab, were preferred over etanercept in ocular and gastrointestinal BD. The improvement rates with any TNF-α inhibitor, adalimumab, infliximab, etanercept, and interferons were 78.5%, 86.1%, 63.4%, 87.5%, and 70%; respectively. The organ-specific improvement rate with TNF-α inhibitors was 76.7% and 70% for ocular and gastrointestinal system involvement. Adverse events have been reported for TNF-α inhibitors, interferons, and rituximab. Six of these were severe [TNF-α inhibitors (n = 4); interferons (n = 2)].

Conclusions: The presented systematic literature search revealed that TNF-α inhibitors followed by interferons were the most frequently used biologic drugs in pediatric BD. Both group of biologic treatments appeared to be effective and have an acceptable safety profile in pediatric BD. However, controlled studies are required for analyzing indications for biologic treatments in pediatric BD.

Background: Bevacizumab-awwb was the first biosimilar approved for cancer treatment in the USA. Limited information is available on the real-world comparative safety and effectiveness of bevacizumab biosimilars, especially for indications granted approval through extrapolation.

Objective: To evaluate the real-world outcomes of patients with metastatic colorectal cancer (mCRC) initiated on bevacizumab-awwb versus bevacizumab reference product.

Patients and methods: This was an observational, longitudinal cohort study of US adult patients with mCRC from four integrated care delivery systems who were newly initiated on bevacizumab-awwb between 1 July 2019 and 30 March 2020 or bevacizumab reference product between 1 July 2015 and 30 June 2018. Patients were followed until 1 year after treatment initiation, end of plan membership, or death, whichever occurred first. The primary outcome of overall survival (OS) was analyzed using a binary non-inferiority test with lower margin of 10% and adjusted Cox proportional hazards regression analysis to assess all-cause mortality if non-inferiority was met. Secondary outcomes included counts of doses received, treatment duration, all-cause hospitalizations, and incidence of serious adverse events.

Results: A total of 1445 patients initiated on either bevacizumab-awwb (n = 239) or bevacizumab reference product (n = 1206) were included in the analysis. The mean overall age was 60 ± 13 years, 46% of patients were female, and 51% were white. The OS rate was 72.8% and 73.1% for patients receiving bevacizumab-awwb and bevacizumab reference product, respectively (p < 0.01 for non-inferiority). The adjusted hazard ratio for mortality was 1.01 (0.77-1.33, p = 0.93). There were no statistically significant differences in secondary outcomes between the study groups.

Conclusions: These findings suggest that bevacizumab-awwb is as effective and safe as bevacizumab reference product for the real-world treatment of mCRC.

Background: Several observational studies have reported acute kidney injury from intravitreal anti-vascular endothelial growth factor (anti-VEGF) drugs for retinal diseases. However, systematic reviews and meta-analyses of randomized controlled trials on this critical topic are scant.

Objective: To evaluate acute kidney injury risk associated with intravitreal anti-VEGF drugs in patients with retinal diseases.

Methods: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials on 12 July, 2023, and included randomized controlled trials reporting acute kidney injury between anti-VEGF drugs (e.g., aflibercept, bevacizumab, brolucizumab, and ranibizumab) and controls for retinal diseases (e.g., age-related macular degeneration, polypoidal choroidal vasculopathy, diabetic retinopathy/diabetic macular edema, retinal vein occlusion, and myopic choroidal neovascularization). Data were synthesized by a fixed-effects model for pooling odds ratios (ORs) using the Peto method.

Results: We included 13 randomized controlled trials (four and nine trials for aflibercept and ranibizumab, respectively) with a total of 4282 participants. The meta-analysis indicated intravitreal anti-VEGF drugs did not increase the acute kidney injury risk, compared with controls (odds ratio [OR]: 1.00, 95% confidence interval [CI] 0.49-2.04, I²: 0%), and no differences in the acute kidney injury risk were observed between different anti-VEGF drugs (OR: 1.10, 95% CI 0.27-4.43, I²: 0% for aflibercept; OR: 0.97, 95% CI 0.42-2.22, I²: 0% for ranibizumab) and between different retinal diseases (OR: 4.61, 95% CI 0.07-284.13, I²: not applicable for age-related macular degeneration; OR: 0.90, 95% CI 0.42-1.93, I²: 0% for diabetic retinopathy/diabetic macular edema; OR: 1.57, 95% CI 0.16-15.88, I²: 0% for retinal vein occlusion).

Conclusions: Intravitreal anti-VEGF drugs were not associated with an acute kidney injury risk, regardless of which anti-VEGF drugs (aflibercept or ranibizumab) or retinal diseases (age-related macular degeneration, diabetic retinopathy/diabetic macular edema, or retinal vein occlusion) were involved.

Systematic review protocol registration: PROSPERO CRD42021267854.