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 rela...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 pr...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% ( = 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.
Shafiekhani M, Esmaeili A, Emami FS
… +12 more, Heidari K, Saberi Moghadam N, Badri S, Kouti L, Mohammadpour AH, Hamishehkar H, Gharekhani A, Amini-Pouya M, Zare N, Abdoli F, Jafarzadeh MA, Dashti-Khavidaki S
BACKGROUND: Rabbit anti-thymocyte globulin (rATG) is widely used for induction immunosuppression in kidney transplantation; however, its administration carries some adverse effects. This study aimed to detect the inciden...BACKGROUND: Rabbit anti-thymocyte globulin (rATG) is widely used for induction immunosuppression in kidney transplantation; however, its administration carries some adverse effects. This study aimed to detect the incidence of thromboembolic events (TEEs) after kidney transplantation and the causality relationship between these events and rATG administration as induction therapy. METHODS: This multicenter retrospective study included 654 kidney recipients from six Iranian centers receiving [Thymoglobulin® (rATG-A) or TGlobulin25™ or (rATG-B)]. Outcomes included TEEs within 30 days post-transplant, hematologic adverse effects, and graft-related outcomes. Risk factors were analyzed using multivariable regression. RESULTS: TEEs occurred in 4.9% of patients, with no significant difference between rATG-A (4.0%) and rATG-B (5.9%) ( = 0.26). Independent risk factors included peripheral rATG infusion without heparin ( < 0.001), preexisting thromboembolic risk conditions ( < 0.001), cytomegalovirus (CMV) infection ( = 0.01), and recipient age >40 years ( = 0.02). No inter-band difference in thromboembolic risk was observed (odds ratio = 1.63, 95% confidence interval 0.71-3.76). Delayed graft function, rejection, mortality, and nephrectomy rates showed no inter-group differences. CONCLUSION: TEEs happened in about 5% of the patients. Peripheral administration of rATG without adding heparin, history of underlying diseases predisposing to TEEs, CMV infection, and recipient age over 40 years were found as risk factors for the occurrence of TEEs.
INTRODUCTION: This systematic review and meta-analysis aimed to compare the efficacy, safety, and immunogenicity of biosimilars and reference biologics (adalimumab, etanercept, infliximab) in the treatment of ankylosing...INTRODUCTION: This systematic review and meta-analysis aimed to compare the efficacy, safety, and immunogenicity of biosimilars and reference biologics (adalimumab, etanercept, infliximab) in the treatment of ankylosing spondylitis (AS). METHODS: We conducted a systematic search of four electronic databases through 6 January 2025, supplemented by trial registry searches for unpublished trials. We included head-to-head randomized controlled trials (RCTs) that compared biosimilars with reference biologics in patients with AS. Effect measures were summarized using random-effects meta-analysis, and the risk of bias was assessed using the Cochrane RoB 2 tool. The overall certainty of evidence was assessed using the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) system. RESULTS: Six head-to-head RCTs (2,107 participants) were included. Biosimilars demonstrated similar efficacy to reference biologics in achieving ASAS20 (risk ratio [RR] 1.01, 95% confidence interval [CI] 0.96-1.07) and ASAS40 (RR 1.00, 95% CI 0.94-1.05) responses. No significant differences were observed in other efficacy (e.g. disease activity indices), safety (e.g. adverse events), or immunogenicity outcomes (e.g. anti-drug antibodies). Sensitivity and subgroup analyses confirmed the robustness of these findings. CONCLUSIONS: This study provides evidence supporting the clinical equivalence of biosimilars to reference biologics in AS treatment, reinforcing their potential as safe and effective alternatives. PROTOCOL REGISTRATION: www.crd.york.ac.uk/prospero identifier is CRD42024528886.
INTRODUCTION: Biosimilars promote price competition, improving affordability and access to biologics without compromising on quality, efficacy, and safety. Biosimilar approvals initially followed a cautious approach, wit...INTRODUCTION: Biosimilars promote price competition, improving affordability and access to biologics without compromising on quality, efficacy, and safety. Biosimilar approvals initially followed a cautious approach, with regulatory requirements developed independently across jurisdictions, complicating global development and increasing costs. Advancements in analytical sciences and two decades of accumulated experience with biosimilar approvals offer an opportunity to reevaluate regulatory requirements. AREAS COVERED: A structured literature review was conducted using PubMed, Embase, and Web of Science, to identify challenges related to biosimilarity demonstration, offer a comprehensive understanding of regulatory requirements for biosimilars globally, and identify opportunities for regulatory convergence. Following title, abstract, and full-text screening, 61 articles were included. EXPERT OPINION: Biosimilar guidelines from stringent regulatory authorities such as EMA and USFDA are robust, yet further alignment of regulatory standards in the US and EU is possible to reflect scientific progress and clinical experience. Regulatory requirements for biosimilars in emerging markets appear to be disproportionate to scientific advancements and accumulated knowledge with biosimilars approval and clinical experience. Global harmonization of biosimilar guidelines, based on gained developments and regulatory experience, could accelerate development and approval process. This would facilitate earlier and enhanced access to safe and affordable biologics.
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...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,...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: SB17 is a ustekinumab (UST) biosimilar targeting interleukin-12/23 for treating immune-mediated inflammatory diseases (IMIDs). The development of UST biosimilars like SB17 may help address the high cost of...INTRODUCTION: SB17 is a ustekinumab (UST) biosimilar targeting interleukin-12/23 for treating immune-mediated inflammatory diseases (IMIDs). The development of UST biosimilars like SB17 may help address the high cost of innovator biologics, offering affordable alternatives without compromising efficacy or safety. AREAS COVERED: This review encompasses the totality of evidence supporting SB17's similarity to UST, its regulatory approval, and indication extrapolation. It also discusses SB17's lower immunogenicity relative to UST. EXPERT OPINION: The approval of UST biosimilars represents a significant advancement in managing chronic IMIDs including psoriasis, plaque psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis, providing cost-effective, efficacious alternatives. A randomized double-blind 28-week study involving over 500 patients with moderate-to-severe chronic plaque psoriasis demonstrated SB17's equivalence to UST, with more than 80% of patients achieving over 90% improvement in psoriasis severity indices. Treatment-emergent adverse events were comparable between SB17 and UST. Despite their potential to transform clinical outcomes, economic burdens, and drug utilization patterns, the adoption of UST biosimilars faces challenges, including concerns about equivalence and regulatory inconsistencies. Addressing these issues through education, consistent regulatory frameworks, real-world data, and ongoing monitoring is crucial for their successful integration into clinical practice.
INTRODUCTION: Ulcerative colitis (UC) includes a dysregulated immune response. The conventional therapy includes immunosuppressants, and biologics targeting inflammatory mediators, but these are often inadequate, or subj...INTRODUCTION: Ulcerative colitis (UC) includes a dysregulated immune response. The conventional therapy includes immunosuppressants, and biologics targeting inflammatory mediators, but these are often inadequate, or subjects become unable to tolerate them. AREAS COVERED:QUASAR: the induction and maintenance components of the phase 3 trial of guselkumab, which inhibits IL-23 by dual mechanisms, in subjects with moderate-to-severe UC. QUASAR enrolled those that had an inadequate response and/or intolerance to corticosteroids, immunosuppressants, biologics, or Janus kinase (JAK) inhibitors. In both parts of the trial, guselkumab improved clinical remission with no excess of adverse events. EXPERT OPINION: For those enrolled throughout, after the maintenance part, the benefit with guselkumab on clinical remission was 24% percentage points (45 vs 21%), which is relatively small. There is no direct comparison of guselkumab with other IL-23 inhibitors in UC. Indirectly comparing trials suggests the clinical remission rates at the end of the trials was higher with guselkumab than with the other approved IL-23, inhibitors, mirikizumab or risankizumab (17 or 15% points, respectively). Thus, guselkumab may be more efficacious than the other 1 L-23 antagonists, possibly due to its additional action to block the CD64 receptor. However, this needs to be tested in a direct comparison trial.
INTRODUCTION: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, by preventing the degradation of LDL receptors, either through interference in the binding of PCSK9 to LDL receptors or through silencing of...INTRODUCTION: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, by preventing the degradation of LDL receptors, either through interference in the binding of PCSK9 to LDL receptors or through silencing of PCSK9 at a molecular level, have revolutionized lipid-lowering treatment and offer the opportunity to further improve clinical outcomes for patients with hypercholesterolemia. AREAS COVERED: We discuss the role of PCSK9 as a therapeutic target for hypercholesterolemia, describe the pharmacodynamics, pharmacokinetics, and metabolism of recaticimab, and report the recent clinical trials with this 'humanized' IgG1 monoclonal antibody (mAb) against PCSK9. EXPERT OPINION: Recaticimab has a high affinity for PCSK9 that confers a prolonged duration of action. Recaticimab durably decreases LDL-cholesterol, non-HDL-cholesterol and apoB, but can also lower Lp(a). Recaticimab may offer advantages over current mAbs in clinical use in terms of its long half-life, dosing interval of up to 12 weeks, and potentially a lower cost; however, long-term concerns regarding immunogenicity remain. Longer-term studies in a variety of more diverse patient cohorts will be needed to further evaluate the efficacy, safety, and durability of recaticimab and to ascertain the optimal dosing schedule for cardiovascular outcome studies.
INTRODUCTION: Epidermal growth factor receptor (EGFR) mutations represent targetable alterations in non-small cell lung cancer (NSCLC). The treatment landscape in the frontline setting for patients with advanced -mutated...INTRODUCTION: Epidermal growth factor receptor (EGFR) mutations represent targetable alterations in non-small cell lung cancer (NSCLC). The treatment landscape in the frontline setting for patients with advanced -mutated NSCLC is evolving with increasing treatment options. EGFR tyrosine kinase inhibitors (TKIs) have significantly improved outcomes, but resistance inevitably develops, necessitating alternative strategies. AREAS COVERED: Patritumab deruxtecan is a novel antibody-drug conjugate targeted human epidermal growth factor receptor-3 (HER3), delivering a topoisomerase-I inhibitor payload to HER3-expressing cancer cells. Phase I and II studies have demonstrated efficacy in patients with -mutant NSCLC with disease progression after prior therapies, including third-generation EGFR TKIs and platinum-based chemotherapy. The phase-II trial reported an objective response rate of 39% and a median progression-free survival of 5.5 months. Patritumab deruxtecan is associated with notable toxicities, including grade 3 and higher hematologic adverse events, gastrointestinal toxicity, and interstitial lung disease (ILD). ILD occurred in 5.3% of patients in the Phase-II study. Early detection and management are crucial for minimizing the risk of complications. EXPERT OPINION: Patients with advanced EGFR-mutant NSCLC who have received TKI therapy and chemotherapy have limited treatment options. Patritumab deruxtecan demonstrates clinical activity in this population with manageable side effects, addressing an unmet need for patients.
INTRODUCTION: Latin American (LatAm) countries face significant increases in healthcare expenditure, driven largely by population growth and aging, and the rising prevalence of cancer and other chronic diseases. Growing...INTRODUCTION: Latin American (LatAm) countries face significant increases in healthcare expenditure, driven largely by population growth and aging, and the rising prevalence of cancer and other chronic diseases. Growing demand and high costs of biologic medicines present barriers to patient access in this region. Biosimilars can improve the affordability and accessibility of biologics, supporting long-term healthcare sustainability. However, their uptake in LatAm has generally been slow. AREAS COVERED: Challenges and barriers to the use of biosimilars and potential strategies to increase biosimilar uptake in LatAm, drawing on learnings from Europe and the U.S.A. EXPERT OPINION: Potential initiatives to drive biosimilar uptake across LatAm include (1) harmonized regulatory processes for biosimilars, with reimbursement policies that prioritize their use and incentives to encourage prescribing; (2) education for key stakeholders to limit misinformation about biosimilars, provide reassurance about safety and efficacy, and increase understanding and acceptance; (3) simplified health technology assessment processes for biosimilars that expedite or adapt some aspects of the traditional approach; and (4) coordinated regional efforts to enable national healthcare systems to purchase medicines in the most cost-effective way, with value frameworks to support decision-making and the implementation of centralized purchasing, competition policies, and risk-sharing agreements.
BACKGROUND: Many ulcerative colitis (UC) patients require the use of second-line agents after the failure of anti-TNF therapy. RESEARCH DESIGN AND METHODS: We conducted a multicenter, retrospective study including 683 ch...BACKGROUND: Many ulcerative colitis (UC) patients require the use of second-line agents after the failure of anti-TNF therapy. RESEARCH DESIGN AND METHODS: We conducted a multicenter, retrospective study including 683 chronically active, moderate-to-severe UC patients who failed first-line anti-TNFs. The rate of treatment persistence and colectomy-free survival was assessed up to 3 years after the initiation of second-line therapy. Predictors for colectomy and persistence were investigated. RESULTS: After the failure of the first-line anti-TNF, ustekinumab had superior persistence and colectomy-free survival rates compared to tofacitinib ( = 0.05; = 0.001) and vedolizumab ( = 0.02; = 0.05), but significant difference was only found in persistence rates in comparison with anti-TNFs ( < 0.001). Regardless of the number of prior anti-TNFs, significantly higher persistence ( = 0.05) and colectomy-free survival rates ( = 0.01) were observed over 2 years with ustekinumab than with vedolizumab or tofacitinib, whereas ustekinumab's superiority over tofacitinib seemed to disappear by the third year. Hypoalbuminaemia ( = 0.002) and shorter disease duration at second-line initiation ( = 0.03) increased, while concomitant immunomodulators ( = 0.05) reduced the risk for colectomy. Shorter disease duration ( = 0.01) and primary non-response to the previously used anti-TNF ( < 0.001) negatively influenced persistence with second-line non-TNF-targeted agents. CONCLUSION: After first-line anti-TNF failure, switching to a non-anti-TNF agent is worth considering in moderate-to-severe UC.
INTRODUCTION: Autoimmune neuro-ophthalmic disorders encompass a diverse array of conditions, including thyroid eye disease (TED), myasthenia gravis (MG), optic neuropathy due to giant cell arteritis (GCA), and optic neur...INTRODUCTION: Autoimmune neuro-ophthalmic disorders encompass a diverse array of conditions, including thyroid eye disease (TED), myasthenia gravis (MG), optic neuropathy due to giant cell arteritis (GCA), and optic neuritis related to multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). While traditional treatments have shown efficacy in managing symptoms, the rapid emergence of biologic therapies has brought forth new avenues for targeted intervention, revolutionizing treatment approaches for these conditions. AREAS COVERED: This review highlights the pathophysiologic pathways and FDA-approved biologic therapies utilized in the management of autoimmune neuro-ophthalmic disorders. We explore multiple therapeutic approaches for autoimmune neuro-ophthalmic disorders, including IGF-1 R antagonism, IL-6 inhibition, complement inhibition, FcRn targeting, B-cell depletion and T-cell modulation. Literature from clinical trials, observational studies, and meta-analyses through 2024 was evaluated to assess efficacy, safety, and long-term outcomes. EXPERT OPINION: Biologic therapies represent a significant advancement in autoimmune neuro-ophthalmic disorders, offering targeted approaches with improved efficacy and safety profiles compared to traditional treatments. Ongoing developments in biomarker identification and delivery systems suggest an increasingly personalized approach to treatment. Future advances will likely focus on optimizing patient selection, reducing costs, improving accessibility, and developing novel therapeutic targets.
INTRODUCTION: Psoriasis is a chronic inflammatory skin disorder with a significant global burden, impacting patients both physically and psychologically. While its exact etiology remains unclear, genetic predisposition a...INTRODUCTION: Psoriasis is a chronic inflammatory skin disorder with a significant global burden, impacting patients both physically and psychologically. While its exact etiology remains unclear, genetic predisposition and environmental triggers play key roles. AREAS COVERED: Biologic therapies have revolutionized psoriasis management, offering targeted and effective disease control. However, despite their proven benefits, these treatments remain underutilized, limiting optimal outcomes and contributing to disparities in care. This expert consensus examines current challenges in biologics use and provides evidence-based recommendations for managing moderate-to-severe psoriasis in Saudi Arabia. EXPERT OPINION: Optimizing biologic therapy use is crucial for improving patient outcomes and reducing disease burden. By addressing gaps in clinical practice, this consensus aims to streamline management approaches and reduce treatment disparities in Saudi Arabia.