Expert Opinion on Biological Therapy最新文献

Introduction: Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of subcutaneous and/or submucosal swelling (angioedema). Current HAE-specific medications primarily focus on either inhibiting plasma bradykinin or kallikrein, or replacing C1-esterase inhibitor, but they are frequently limited in efficacy and accessibility. In contrast, Factor XII (FXII) inhibitors may provide a novel therapeutic approach by targeting the contact system at an upstream level, potentially addressing some of these limitations.

Areas covered: This review explores the role of FXII in HAE and assesses FXII inhibition as a promising prophylactic treatment strategy. By synthesizing findings from both preclinical and clinical studies and real-world observational studies, the review highlights the efficacy, safety, and practical benefits of FXII inhibitors, such as garadacimab.

Expert opinion: FXII inhibition represents a promising new strategy for HAE management and may address current unmet needs in prophylactic therapies. The early experiences of garadacimab highlights FXII as a viable and druggable target, paving the way for broader applications in bradykinin-mediated disorders. Despite its potential, uncertainties remain regarding long-term safety, cost, and accessibility. Future research will help redefine the role of FXII inhibition in advancing personalized care and improving the quality of life for patients with HAE.

Introduction: This systematic review and meta-analysis evaluated the lipid-lowering efficacy and safety of evolocumab in statin-treated patients at high cardiovascular risk, focusing on changes in LDL-C, TG, ApoB, HDL-C, and Lp(a) after 12 weeks.

Methods: A comprehensive search identified randomized controlled trials comparing evolocumab to placebo in adults on statin therapy. Studies reporting baseline and 12-week lipid and safety data were included. Risk of bias was assessed using the Cochrane tool. Random-effects models were used to calculate mean differences (MD) or odds ratios (OR) with 95% confidence intervals (CI).

Results: Five trials with 4,009 participants were analyzed. Evolocumab significantly reduced LDL-C (MD: -64.67; 95% CI: -66.72 to -62.61), TG, ApoB, and Lp(a), and increased HDL-C. No significant difference was observed in total TEAEs (OR: 0.97; 95% CI: 0.84 to 1.14) or serious TEAEs (OR: 1.23; 95% CI: 0.80 to 1.89) versus placebo.

Conclusions: Evolocumab offers robust lipid-lowering benefits with a safety profile comparable to placebo in statin-treated patients. Limitations include short follow-up and variable statin regimens. Further long-term studies are needed to confirm cardiovascular outcome benefits.

Protocol registration: www.crd.york.ac.uk/prospero identifier is CRD42024543525.

Introduction: Denileukin difitox (DD), a recombinant cytotoxic fusion protein composed of full-length human interleukin-2 (IL-2) conjugated to diphtheria toxin's A and B subunits, has shown activity in patients with relapsed and refractory (R/R) mycosis fungoides and the Sezary Syndrome (MF/SS) whose tumor cells expressed CD25, with response rates of 30-44% in advanced and earlier (Stage I-III) stage patients, respectively.

Areas covered: Recently, a newer version of DD with improved purity and bioactivity (DD-cxdl) was developed. A registrational trial of D-cxdl showed similar response rates in R/R MF/SS. The purpose of this review is to describe efficacy and safety data surrounding these medications and highlight the equivalency of these two drugs.

Expert opinion: Both DD and DD-cxdl demonstrate activity in R/R MF/SS with higher response rate in tumor and plaque stage disease. Adverse events grade ≥3 included infusion reactions in 8%, elevated hepatic transaminases in 22%, and capillary leak syndrome in 8%. In addition to direct targeting of CD25 expressing tumor cells, both drugs are also capable of depleting immunoregulatory T-cells. A clinical trial of DD-cxdl in Japan showed that responses were independent of CD25 expression, suggesting multiple mechanisms of action for DD-cxdl in MF/SS and potentially other malignancies.

Background: The impact of traditional systemic drugs to treat psoriasis (ciclosporin, methotrexate, and acitretin) in a subsequent response to biologics has not been adequately addressed in the literature. In clinical practice, it is increasingly necessary to initiate, due to concomitant comorbidities, biologics in patients with psoriasis or psoriatic arthritis (PsA) who have not undergone prior treatment with systemics, i.e. full-naive.

Objectives and methods: This study analyzed the possible impact of non-biological systemic therapies on the effectiveness and drug survival of first-line biologic drug up to 12 months in bio-naive psoriatic and PsA patients consecutively enrolled from January 2017 to March 2021.

Results: Ninety-five patients with severe psoriasis (13.5%) were full-naive. Being full-naive and having or not having undergone methotrexate or cyclosporine therapy did not impact response to subsequent years of biologic therapy. Only acitretin promotes faster response to subsequent biologic drugs with 59.6% and 74.2% of patients achieving Psoriasis Area Severity Index (PASI) 90 at 16 and 28 week, respectively, vs. 50.5% and 65% (p = 0.034 and 0.026). In multivariate analysis, the advantage given by acitretin was lost.

Conclusion: Previous systemic therapy in bio-naive patients does not appear to result in a differential response to biologics during the first year of treatment.

Background: This study compared efficacy, pharmacokinetics (PK), immunogenicity, and safety between AVT06, proposed biosimilar to reference product (RP) aflibercept (Eylea®), in participants with neovascular age-related macular degeneration (nAMD).

Methods: In this randomized, double-masked, multicenter, active-controlled trial, treatment naïve participants received intravitreal injections of AVT06 or RP (2 mg) over 48 weeks. The primary endpoint was the change from baseline to Week 8 in best-corrected visual acuity (BCVA). Secondary endpoints included BCVA improvements and changes in Central Subfield Thickness (CST). PK, immunogenicity, and safety were also assessed.

Results: The 90% and 95% confidence intervals (-0.60, 2.14 and -0.86, 2.40, respectively) in least squares mean difference in BCVA letter score from baseline to Week 8 were contained within the pre-specified equivalence margin of ETDRS BCVA letter score of [-3.5 to 3.5], supporting the demonstration of comparative efficacy. Secondary efficacy outcomes were also comparable. PK analyses supported systemic safety. There were no clinically meaningful differences in immunogenicity profiles. Safety profiles were similar; most treatment-emergent adverse events were mild and unrelated to the study drug.

Conclusions: Results supported a demonstration of comparable efficacy between AVT06 and RP aflibercept. Similar PK, immunogenicity, and safety profiles were also shown.

Clinical trial registration: ClinicalTrials.gov identifier is NCT05155293; ClinicalTrialsRegister.eu identifier is 2021-003651-42.

Introduction: Despite recent treatment breakthroughs, non-small cell lung cancer (NSCLC) remains the highest cause of cancer-related mortality. New therapies are urgently needed, particularly in patients without actionable genomic alterations (AGAs), who currently receive a combination of chemotherapy and anti-PD1/PD-L1 therapy. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate combining an antibody against Trop-2 and an exatecan payload which has shown activity in both breast cancer and NSCLC. With several drugs in this class, it is important to understand their activity and limitations in different subtypes of NSCLC.

Areas covered: The literature was reviewed for trials demonstrating activity of their preliminary and/or final results, Dato-DXd, was studied across multiple clinical trials, including the Phase 1 TROPION-PanTumor01 and Phase 3 TROPION-Lung01 studies that are deemed pivotal in demonstrating its efficacy across different patients.

Expert opinion: Dato-DXd is a promising new option for NSCLC treatment with clear evidence of activity, shown early signals of efficacy, particularly in non-squamous NSCLC and patients with AGAs. However, patient selection remains paramount for future clinical development. Further research is necessary to optimize dosing strategies, manage adverse events, and better understand its role in both frontline and relapsed/refractory treatment settings as part of combination therapy, as well as neoadjuvant therapy prior to surgery.

Introduction: There has been a giant leap forward in the management of Hodgkin's lymphoma (HL) over the past decade. Emergence of long-term data from large, randomized trials in early-stage disease (eHL) and incorporation of brentuximab vedotin (BV) or nivolumab into the frontline setting through three large phase-3 trials in advanced stages (aHL) are driving the paradigm shift in HL. The new landscape promises chances of cure to over 90% newly diagnosed patients while maintaining caution for long-term toxicity.

Areas covered: This review will cover the published evidence regarding primary analyses or updates within the last 5 years on phase-3 clinical trials conducted in the frontline treatment setting for HL. Concerning areas of clinical significance where no comparative trial data is available, data from phase-2 trials or real-world analyses will be briefly discussed.

Expert opinion: Consolidative radiotherapy is no longer a strict necessity in eHL cases with complete response to frontline chemotherapy and the decision to irradiate in such cases should be individualized. The state-of-the-art in managing aHL requires the use of either BV or nivolumab as introduced by the GHSG HD21 and SWOG S1826 trials, respectively.

Introduction: Psoriasis is a chronic, systemic inflammatory disease with significant physical and psychosocial burden. Advances in understanding the pathogenesis of psoriasis, particularly the role of interleukin (IL)23/Th17 axis, have led to the development of selective drugs targeting these cytokines. Among these, IL23 inhibitors (guselkumab, risankizumab, and tildrakizumab), represent the most recent class of biologic drugs approved for the management of moderate-to-severe plaque psoriasis. Since their approval, real-life data on the use of anti-IL23 have confirmed their high efficacy, durability, and favorable safety profile.

Areas covered: This narrative review summarizes real-world data on the effectiveness, also in difficult-to-treat areas, safety, and drug survival of IL23 inhibitors in psoriasis.

Expert opinion: Real-world evidence consistently confirms the strong efficacy, favorable safety profile, and long-term treatment durability of IL23 inhibitors across various patient subgroups, including those with comorbidities, prior biologic failures, and the involvement of difficult-to-treat areas. IL23 inhibitors have become key components of the therapeutic arsenal in psoriasis, and their performance in real-world settings continues to support their widespread adoption in clinical practice.