Expert Opinion on Biological Therapy

Introduction: BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) represent a significant therapeutic challenge in the treatment of bladder cancer. Nadofaragene firadenovec, represents a breakthrough in this area, offering a novel approach for the treatment of BCG-unresponsive NMIBC. Areas covered: This overview explores the historical development of nadofaragene firadenovec, assessing its efficacy and safety, and discusses future NMIBC therapy directions. Expert opinion: Patients with high grade NMIBC who are BCG unresponsive will have a growing number of treatment alternatives to bladder removal. Nadofaragene firadenovec offers good short-term efficacy but lacks significant durability for most patients. Its strengths include ease of administration and low risk of adverse events. This will need to balance with risk of progression and cost. Furthermore, the likely approval of other agents will require consideration of which therapy to use and for which patient. The need for biomarkers to tailor treatment choices to individual patient needs is becoming more critical. The treatment field is rapidly advancing, with several Phase 3 single-arm trials underway, indicating a potential broader range of treatment options for NMIBC. Further research will be necessary to determine the optimal choice for patients.

Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory rheumatic disease that affects both the articular and extra-articular structures, leading to significant joint damage, disability and excess mortality. The treatment algorithm of RA has changed tremendously in the past 1-2 decades because of the emergence of novel biological therapies that target different mechanisms of action in addition to TNFα. Areas covered: This article summarizes the evidence and safety of the non-TNF biological DMARDs in the treatment of RA, including those that target B cells, T-cell co-stimulation, interleukin (IL)-6 and granulocyte-monocyte colony-stimulating factor (GM-CSF). The targeted synthetic DMARDs such as the Janus kinase inhibitors are not included. The availability of the less costly biosimilars has enabled more patients to receive biological therapy earlier in the course of the disease. The evidence for the non-TNF biosimilar compounds in RA is also reviewed. Expert opinion: There are unmet needs of developing novel therapeutic agents to enhance the response rate and provide more options for difficult-to-treat RA. These include the newer generation biologic and targeted synthetic DMARDs. A personalized treatment strategy in RA requires evaluation of the cellular, cytokine, genomic and transcriptomic profile that would predict treatment response to biologic or targeted DMARDs of different mechanisms of action.

Introduction: There is a need for new therapies that can enhance response rates and broaden the number of cancer indications where immunotherapies provide clinical benefit. CD40 targeting therapies provide an opportunity to meet this need by promoting priming of tumor-specific T cells and reverting the suppressive tumor microenvironment. This is supported by emerging clinical evidence demonstrating the benefits of immunotherapy with CD40 antibodies in combination with standard of care chemotherapy. Areas covered: This review is focused on the coming wave of next-generation CD40 agonists aiming to improve efficacy and safety, using new approaches and formats beyond monospecific antibodies. Further, the current understanding of the role of different CD40 expressing immune cell populations in the tumor microenvironment is reviewed. Expert opinion: There are multiple promising next-generation approaches beyond monospecific antibodies targeting CD40 in immuno-oncology. Enhancing efficacy is the most important driver for this development, and approaches that maximize the ability of CD40 to both remodel the tumor microenvironment and boost the anti-tumor T cell response provide great opportunities to benefit cancer patients. Enhanced understanding of the role of different CD40 expressing immune cells in the tumor microenvironment may facilitate more efficient clinical development of these compounds.

Background: Switch patterns among different biologics and from originators to biosimilars (and vice versa) can be complex in patients with psoriasis (PsO) and psoriatic arthritis (PsA). Objective: The aim of this study was to describe switching patterns of biological drugs in PsO/PsA patients and to explore predictors of multiple switches and switch-back. Research design and methods: A large-scale retrospective cohort study was conducted using the Italian VALORE database. Bio-naïve users treated for PsO/PsA during 2010-2022 were included. Time to switch/swap and predictors of multiple switches and switch-back were analyzed. Results: Thirty-thousand seven hundred bio-naïve users were included. At 3 and 5 years of follow-up, patients with at least one switch/swap were 37.1% and 47.8%, respectively. The median time to first switch/swap was significantly shorter (p< 0.001) for TNF-α inhibitors (2,068 days) than anti-IL (2,780 days). At 1 year of follow-up patients starting with IL-23 switched/swapped biological therapy less frequently than those with anti-IL-12/23 and anti-IL-17 (4.9% vs. 8.7% and 9.4%, respectively). Patients starting with anti-IL-12/23 reported a significantly lower risk of multiple switches and switch-back (0.74, 95% CI, 0.67-0.83; 0.58, 95% CI, 0.44-0.77, respectively) than those with TNF-α inhibitors. Conclusions: Patients with PsO/PsA starting with TNF-α inhibitors switch/swap more rapidly and frequently than those with anti-IL, which are also associated with a reduced risk of multiple switches during follow-up.

Introduction: Gain/amplification of 1q (+1q) represents one of the most prevalent cytogenetic abnormalities (CAs) observed in multiple myeloma (MM). Historical studies predating the advent of anti-CD38 monoclonal antibodies (moAbs) implicated + 1q in poor prognoses, prompting its integration into novel staging systems. However, with the emergence of daratumumab and isatuximab, two pivotal anti-CD38 moAbs, the landscape of MM therapy has undergone a profound transformation. Areas covered: This review encompasses a comprehensive analysis of diverse study methodologies, including observational investigations, clinical trials, meta-analyses, and real-world database analyses. By synthesizing these data sources, we aim to provide an overview of the current understanding of + 1q in the context of anti-CD38 moAbs therapies. Expert opinion: Despite the paucity of available data, evidence suggests a potential mitigating effect of daratumumab on the adverse prognostic implications of + 1q. However, this benefit seems to diminish in patients harboring ≥ 4 copies or with concurrent high-risk CAs. On the other hand, isatuximab demonstrated promising outcomes in the relapsed-refractory setting for + 1q MM patients. Nevertheless, direct comparison between the two compounds is currently challenging. The current evidence firmly supports the integration of anti-CD38 moAb-based therapies as the standard of care for + 1q patients, pending further elucidation.

Background: This study aimed to assess the efficacy and safety of MW031 in Chinese postmenopausal women with osteoporosis. Patients and methods: In this randomized, double-blind, placebo-controlled, multicenter clinical trial, 448 postmenopausal women with osteoporosis were randomized 3:1 to receive MW031 and placebo for 12 months. The primary efficacy endpoint was the percentage change from baseline in BMD at lumbar spine in month 12. The safety and immunogenicity profiles were also included. Results: Of 448 randomized patients, 421 completed the study (MW031, n = 322; placebo, n = 99).After 12 months of MW031 treatment, BMD increased by 5.80% at lumbar spine,3.65% at total hip, and 2.93% at femoral neck. The model-adjusted difference was 3.86% (P<0.0001), 2.34% (P<0.0001), and 1.05% (p = 0.08) compared with placebo group, respectively. For the bone turnover markers, serum CTX level in MW031 group decreased to the maximum difference in month 1 (-71.71%, 95% CI: -77.83%, -65.60%, P<0.0001) compared with the placebo group. The safety analysis showed no significant differences in the proportion of patients reporting any adverse events between the two groups. Conclusion: This study demonstrated that MW031 safely and effectively increased BMD and rapidly decreased the level of bone resorption marker in Chinese postmenopausal women with osteoporosis. Trial registration: NCT05215977 (ClinicalTrials.gov.).

Introduction: Approximately 50% of patients that receive a CGRP(r) MoAb for the preventative treatment of migraine are expected to discontinue therapy. For patients that discontinue CGRP(r) MoAb therapy, few clinical options are available. One potential option is to switch CGRP(r) MoAbs, however, data concerning the efficacy of this intervention is scarce. Areas covered: This manuscript aims to summarize all available data concerning the potential efficacy of switching CGRP(r) MoAbs following previous medication discontinuation. Data was sourced by completing a database search for the terms: 'CGRP monoclonal antibody switch OR CGRP monoclonal antibody switching.' Expert opinion: While data considering the potential efficacy of CGRP(r) switching continues to grow, our expert opinion supports the most recent European Headache Federation statement regarding CGRP(r) MoAb prescribing practices, concluding that there remains insufficient data to determine the efficacy of this intervention. As this topic is of significant clinical importance, we recommend a call-to-action to expand on current data considering the therapeutic options for patients that discontinue CGRP(r) MoAb therapy.

Introduction: Chronic spontaneous urticaria (CSU) poses significant challenges, especially in pediatric and adolescent patients, impacting physical, emotional, and social well-being. Recent biologic breakthroughs offer promise, however, data on safety and efficacy in this population remain limited. Areas covered: This review examines current biologic treatments in pediatrics and adolescents with CSU and explores the rapidly emerging landscape. Expert opinion: Despite omalizumab's approval for allergic asthma in children since 2009, its delayed approval for CSU raises questions. Ligelizumab, a next-generation anti-IgE mAb, showed effectiveness in adults but lacks pediatric studies. CT-P39, a biosimilar to omalizumab, demonstrates promise, yet adolescent-specific outcomes are undisclosed. Dupilumab's recent approval for atopic dermatitis in children from 6 months onwards signifies progress. Expert opinion underscores the scarcity of controlled trials in pediatric and adolescent CSU, emphasizing the need for comprehensive studies. Age-specific data and collaboration are crucial for addressing research gaps and expanding indications for pediatric CSU treatment. The recently validated UAS7 parameter in children marks a milestone for prospective clinical trials. Despite challenges, the biology therapy outlook for pediatric and adolescent CSU is promising. Importantly, studies indicate that pediatric CSU is at least as prevalent as in adults, highlighting the need for approved treatments in this population.

Introduction: The prognosis for large B-cell lymphoma (LBCL) patients who did not respond or relapsed after chimeric antigen receptor (CAR)-T therapy remains dismal, with no established consensus on the most effective salvage regimen. Methods: We conducted a random-effects meta-analysis of complete response (CR) and overall response rates (ORR) to first-line treatments for CAR-T-relapsed/refractory LBCL. We followed the predefined protocol available at PROSPERO (CRD42023473854). Results: We identified 41 studies evaluating the following interventions: non-CD19 CAR-T, CD19 CAR-T, bispecific antibodies (BiTEs), lenalidomide- and polatuzumab-based regimens, radiotherapy, immune checkpoint inhibitors (ICI), Bruton's Tyrosine Kinase inhibitors (BTKi). Non-CD19 CAR-T cells yielded the best CR (56%, CI: 40-71%), significantly higher than other interventions except CD19 CAR-T (CR = 30%, CI: 7-58%). BiTEs, radiotherapy, lenalidomide- and polatuzumab-based regimens (CR: 28%, 26%, 19%, 24% respectively) did not differ significantly from each other. ICI and BTKi showed the lowest CR rates (12%, CI: 5-20% and 8%, CI: 0-23%, respectively), and were also significantly inferior to BiTEs. ORR was the highest for non-CD19 CAR-T (ORR = 80%, CI: 66-92%), whereas all other regimens yielded values below 50%. Conclusions: Non-CD19 CAR-T cells were associated with higher response rates and should be considered if patients are eligible. Given the heterogeneity of the estimates, the results should be interpreted cautiously. Registration: PROSPERO CRD42023473854.

Introduction: At the 65th American Society of Hematology (ASH) 2023 Annual Meeting, the latest advancements in CD20×CD3 BsAbs for B-cell lymphoma (BCL) were highlighted, particularly in relapsed/refractory (R/R) follicular lymphoma (FL) and R/R diffuse large B-cell lymphoma (DLBCL). Areas covered: This summary highlights some of the major studies on CD20×CD3 BsAbs for BCL. Expert opinion/commentary: CD20×CD3 is the most widely studied BsAb, with promising results in patients with R/R DLBCL and R/R FL ≥ two prior lines of systemic therapy. Trials with the first line of B-cell lymphoma also revealed promising results. Hopefully, BsAb monotherapy or BsAb-containing regimens may become the standard therapy in patients with FL and DLBCL.

Background: The rise of biologic agents has been a major breakthrough in treating immune-mediated inflammatory diseases (IMIDs). However, their high cost underscores the need for strategies to optimize treatment efficiency. Biosimilars offer cost-effective alternatives to biologics. This study aimed to assess biosimilar drug availability's impact on biologic therapy access for IMIDs. Research design and methods: A retrospective observational study in 15 Spanish hospitals analyzed IMID patients (arthropathies, inflammatory bowel disease and psoriasis) initiating biologic therapy with originator or biosimilar drugs (infliximab, etanercept, adalimumab). Time to availability and initiation of biologic therapy were assessed. Results: 267 patients were included, with 58.4% starting on biosimilars. The mean time to availability of the biologic drugs in the hospitals was 15.9 ± 6.7 months, (20.0 ± 12.4 for originator and 11.8 ± 5.2 for biosimilars). Mean time to biologic treatment was 7.7 ± 9.0 years (8.6 ± 8.9 for originators and 7.0 ± 9.0 for biosimilars). Showing statistically significant differences among conditions. Conclusion: The emergence of biosimilar drugs has enhanced market competition and accelerated their adoption into hospitals' therapeutic regimens over original reference drugs. This has significantly improved access to biologic therapy for patients with IMIDs, evidenced by a notable 1.6-year reduction in access time for biosimilar drugs.