Expert Opinion on Biological Therapy最新文献

Introduction: Biosimilars are biologic medications designed to closely replicate the properties of previously approved biologic disease-modifying anti-rheumatic drugs (bDMARDs). They offer a cost-effective alternative once the original product's patent has expired.

Areas covered: In pediatric rheumatology, the use of biosimilars began in 2013 with the launch of the infliximab biosimilar. Since then, more biosimilars, including etanercept, rituximab, and adalimumab, have been introduced, providing additional treatment options for children with rheumatic diseases. This article explores the role of biosimilars in pediatric rheumatology, particularly in juvenile idiopathic arthritis, focusing on their development, safety, and efficacy, as well as the challenges associated with their clinical adoption. It also addresses the importance of education in improving understanding of biosimilars.

Expert opinion: The article provides insights into their safety, effectiveness, and economic impact by reviewing current literature to help healthcare professionals make informed decisions for treating pediatric rheumatic diseases. Education for both patients and healthcare providers, effective communication, and expectation management play a critical role in ensuring appropriate treatment continuity.

Introduction: Antibody-drug conjugates (ADCs) are a rapidly evolving class of anti-cancer drugs with a significant impact on management of hematological malignancies including diffuse large B-cell lymphoma (DLBCL). ADCs combine a cytotoxic drug (a.k.a. payload) attached through a linker to a monoclonal antibody specific to a particular cancer antigen. Payloads include microtubule disruptors or DNA damaging chemicals. After attaching to the antigen, the ADCs are internalized, and the payload is dissociated from ADC by lysozymes and delivered to the intended site for exerting cytotoxic effects. This unique molecular design permits a better balance of efficacy and safety. Loncastuximab tesirine and polatuzumab vedotin are two ADCs approved in the U.S.A. for treatment of DLBCL.

Areas covered: This review covers the efficacy and safety data of these two drugs. We will review new ADC-based combination regimens and novel constructs in development.

Expert opinion: ADCs have made a significant impact in improving outcomes of DLBCL patients. Both polatuzumab vedotin and loncastuximab tesirine are established as useful therapeutics options, with polatuzumab vedotin currently approved in first line and relapsed/refractory setting, while loncastuximab tesirine is approved in relapsed setting. ADCs are effective with tolerable safety profile and currently many more ADCs are undergoing clinical trials.

Introduction: CAR-T therapy has transformed the treatment landscape for relapsed/refractory diffuse large B-cell lymphomas (DLBCL).

Areas covered: This article reviews the existing evidence for using CAR-T therapy as a second-line treatment. Two major phase 3 trials, ZUMA-7 and TRANSFORM, have shown that axi-cel and liso-cel, respectively, offer superior outcomes compared to historical standard chemoimmunotherapy and consolidation with autologous hematopoietic stem cell transplantation (auto-HCT). Additionally, two promising phase 2 trials, PILOT and ALYCANTE, demonstrated the efficacy of CAR-T therapy in patients who are ineligible for auto-HCT. We also reviewed the potential biological factors behind these results.

Expert opinion: Several factors support the use of CAR-T therapy in earlier treatment lines: better T-cell fitness in the infused product, reduced systemic inflammation in patients, and a more favorable tumor microenvironment. Although real-world data for second-line CAR-T therapy is still early, it is expected that CAR-T will be used more widely. Additional focus highlights the need for defining suitable patient populations and the efforts to enhance accessibility and cost-effectiveness of this groundbreaking treatment approach.

Introduction: Approximately 75% of bladder cancer cases are non-muscle invasive at diagnosis. Drug development for non-muscle invasive bladder cancer (NMIBC) has historically lagged behind that of other malignancies. No treatment has demonstrated the ability to overcome drug resistance that ultimately leads to recurrence and progression. Gene therapy is emerging as a promising option for patients with NMIBC.

Areas covered: This review summarizes the clinical application of gene therapy in NMIBC management and discusses recent clinical trials involving the adenoviral vector-based treatment nadofaragene firadenovec, and the oncolytic serotype 5 adenovirus, cretostimogene grenadenorepvec. Nadofaragene received approval by the Food and Drug Administration in December 2022, and cretostimogene has been granted Fast Track Designation and Breakthrough Therapy Designation. Ongoing trials are investigating strategies to augment efficacy and durability of these therapies.

Expert opinion: Gene therapy may overcome resistance mechanisms of other NMIBC treatments, and data suggest a role for combination therapy with additive or synergistic agents. Significant differences in trial design limit comparability of agents across trials, highlighting the need for critical assessment of published findings. While initial investigations were in high-risk patients who recur despite frontline therapy with Bacillus Calmette-Guerin (BCG), there is growing interest in BCG-naïve and intermediate-risk populations.

Introduction: Revolutionary drugs have been developed and approved in the last 5 years for the treatment of hereditary angioedema (HAE). Increased knowledge of HAE pathophysiology has led to the development of innovative drugs for self-administered on-demand therapy and for short- and long-term prophylaxis (LTP). This has rendered possible a personalized approach for patients, allowing greater control of symptoms, better quality of life and reduction in the incidence of adverse effects linked to old treatments.

Areas covered: In this review we have highlighted which treatments are currently approved for HAE and some of the promising future therapies under development.

Expert opinion: While the first generation of approved treatments improved disease control for most patients, innovative therapies may allow individualized action plans and reduce complexity of treatment. Switching therapies due to insufficient efficacy, patient preference or adverse events is becoming progressively feasible and common. New LTPs may lead to the achievement of attack-free remission, allowing us to hopefully reach complete disease control for all patients and further improving their quality of life. In particular, LTPs with longer administration intervals, and on-demand therapies administered via the oral route will have a key role and will set more prominent targets for the upcoming drugs.

Introduction: Atopic dermatitis (AD) is a common chronic inflammatory skin disease. Moderate-to-severe AD severely affects patients' quality of life. New drugs selectively targeting molecular pathways involved in the pathogenesis of the disease led to a new era for the treatment of AD. However, the current available options are limited and do not completely fulfill patients' needs. Recently, lebrikizumab, a new humanized monoclonal antibody targeting IL-13, has been approved for treating moderate-to-severe AD.

Areas covered: By analyzing scientific literature reporting lebrikizumab phase 3 pivotal clinical studies and summarizing recent advances in AD pathogenesis, in this article we focused on the mechanism of action of lebrikizumab in comparison to other biologics used for treating AD and discussed clinical data that led to the approval of this biologic agent.

Expert opinion: Among biologics approved for moderate-to-severe AD, lebrikizumab is characterized by a unique mechanism of action and an attractive maintenance regimen, besides good efficacy and safety profiles. Moreover, clinical evidence suggests that patients naïve or pre-treated with other biologics and affected by AD localized in sensitive areas and by type 2 comorbidities might be successfully treated with lebrikizumab.

Background: Monitoring biologic drug therapy during pregnancy in women with immune-mediated inflammatory diseases (IMIDs) is crucial to ensure treatments align with evidence-based practices.

Research design and methods: A retrospective cohort study based on healthcare claims data from eight Italian regions was conducted, analyzing deliveries between 2009 and 2021. The study included women receiving biologic drugs within nine months before their last menstruation. Exposures to biologics, conventional disease-modifying anti-rheumatic drugs (DMARDs) and symptom-relieving medications were assessed in the trimesters (T) before, during and after pregnancy. Factors influencing biologic treatment persistence during pregnancy were analyzed.

Results: A cohort of 1,763 deliveries was considered. Biologic drugs were prescribed for rheumatic (33.6%), dermatological (32.6%), and gastrointestinal diseases (28.4%). Biologic use declined during pregnancy (TI = 37.3%; TII = 17.6%; TIII = 11.3%), increasing again postpartum. During pregnancy, there was increased use of symptom-relieving medications for rheumatic diseases and DMARDs for gastrointestinal diseases. Factors associated with continued biologic treatment included being older than 35 years and the region of delivery.

Conclusions: This study found a decrease in biologics drug use during pregnancy and highlights the necessity for personalized therapeutic approaches. Geographic variations in biologic drug use emphasize the need for educational initiatives about the risk-benefit profiles of these therapies during pregnancy.

Introduction: The remarkable ability of human pluripotent stem cells (hPSCs) to differentiate into specialized cells of the human body emphasizes their immense potential in treating various diseases. Advances in hPSC technology are paving the way for personalized and allogeneic cell-based therapies. The first-in-human studies showed improved treatment of diseases with no adverse effects, which encouraged the industrial production of this type of medicine. To ensure the quality, safety and efficacy of hPSC-based products throughout their life cycle, it is important to monitor and control their clinical translation through good practices (GxP) regulations. Understanding these rules in advance will help ensure that the industrial development of hPSC-derived products for widespread clinical implementation is feasible and progresses rapidly.

Areas covered: In this review, we discuss the key translational obstacles of hPSCs, outline the current hPSC-based clinical trials, and present a workflow for putative clinical hPSC-based products. Finally, we highlight some future therapeutic opportunities for hPSC-derivatives.

Expert opinion: hPSC-based products continue to show promise for the treatment of a variety of diseases. While clinical trials support the relative safety and efficacy of hPSC-based products, further investigation is required to explore the clinical challenges and achieve exclusive regulations for hPSC-based cell therapies.

Introduction: Hypercholesterolemia and other lipid disorders are major causes of atherosclerotic cardiovascular disease (ASCVD). Statins have been the mainstay of lipid-lowering therapy for many years, but they may not be adequate to achieve the target low-density lipoprotein (LDL) cholesterol levels and there are other residual lipid risk factors.

Areas covered: This article reviews the biologic therapies in development for hypercholesterolemia identified by a PubMed search. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) is a major focus, but the drugs targeting apolipoprotein C3 (apoC3) and angiopoietin-like 3 (ANGPTL3) that were originally developed to reduce the levels of triglyceride-rich lipoproteins are now being explored to reduce cardiovascular events in a wider range of patients. A brief overview of biologic therapies targeting lipoprotein(a) [Lp(a)] is also proved.

Expert opinion: Inhibition of PCSK9 remains an attractive target. In addition to the currently available monoclonal antibodies (mAbs) and small interfering RNA (siRNA), new mAbs and the adenectin lerodalcibep are promising therapies. The antisense oligonucleotide (ASO) and siRNA inhibitors of apoC3 and ANGPTL3 are effective in severe hypertriglyceridemia and homozygous familial hypercholesterolemia, respectively, and may prove to have wider applications. ASO and siRNA inhibitors of Lp(a) are currently in cardiovascular outcome studies.

Objectives: This analysis reported the incidence of safety endpoints across five phase 3 randomized controlled clinical trials in patients with rheumatoid arthritis (RA), Crohn's disease (CD), and chronic plaque psoriasis (PsO) who received ≥ 1 dose of adalimumab-adbm or adalimumab reference product (RP).

Methods: Exposure-adjusted incidence rates for safety endpoints were calculated per 100 patient-years and reported by disease indication and treatment arm. Subgroup analyses by patient age and sex were also conducted.

Results: The mean length of follow-up was 62 weeks, 48 weeks, and 32 weeks for patients with RA, CD, and PsO, respectively. Rates of serious adverse events (SAEs) and discontinuations due to adverse events (AEs) were similar among patients with RA and PsO, but slightly higher among those with CD. Incidence rates of all safety endpoints were consistent between the adalimumab-adbm and adalimumab RP treatment arms within each indication Subgroup analyses of patients with RA, CD, and PsO showed no between-group differences by age and sex.

Conclusions: In patients with RA, CD, and PsO, there were no differences between biosimilar adalimumab-adbm or the adalimumab RP regarding the rate of AEs, SAEs, discontinuations due to AEs, deaths, or any AEs of special interest.