Letter to the Editor Regarding "Dupilumab Versus Lebrikizumab Demonstrates Greater Likelihood of Achieving and Maintaining Improvements in Efficacy Outcomes Using a Placebo Adjusted Indirect Treatment Comparison".

BACKGROUND: Vedolizumab (VDZ), a gut-selective monoclonal α4β7 integrin antibody, is approved for the treatment of moderately to severely active ulcerative colitis (UC) and Crohn’s disease. Intravenous (IV) VDZ was recently shown to be superior to subcutaneous (SC) adalimumab (ADA) in VARSITY (1), the first head-to-head randomized controlled trial (RCT) of biological therapies in UC. No comparative efficacy or safety data versus ADA exist for VDZ SC, a new formulation in development (2). To generate estimates of the comparative efficacy and safety of VDZ SC versus ADA, we conducted a network meta-analysis (NMA) of RCTs. METHODS: The NMA was conducted using results from a targeted literature review that identified RCTs of both VDZ and ADA: GEMINI 1, VISIBLE 1, ULTRA-2, and VARSITY. In the former two trials, responders were rerandomized at the end of induction, whilst the latter two trials were treat-through designs. To adequately analyze these trials in one network of evidence, efficacy outcomes were assessed conditionally upon response at start of maintenance. For treat-through studies, this was response at 6/8 weeks. Efficacy outcomes in the maintenance period were response and remission at 52/54 weeks. Safety outcomes were overall adverse events (AEs), serious AEs (SAEs), overall infections, serious infections, and AEs leading to discontinuation as reported at 52 weeks. Odds ratios (OR) with 95% credible intervals (CrI) were estimated using probit and binomial NMA models. ADA SC 40 mg Q2W, VDZ IV 300 mg Q4W, and VDZ IV 300 mg Q8W were all compared against VDZ SC 108 mg Q2W (reference group). RESULTS: ADA had lower rates for maintenance of response and remission relative to VDZ SC, but this was not statistically significant (ORs with 95% Crl: 0.60 [0.33, 1.08] and 0.59 [0.33, 1.09], respectively). Although overall AEs were significantly higher with ADA compared with VDZ SC (OR 2.02 [1.04, 3.89]), other safety outcomes were similar: overall infections, OR 1.86 (0.94, 3.77); serious AEs, OR 1.41 (0.54, 3.75); serious infections, OR 0.39 (0.05, 2.73); AEs leading to discontinuation, OR 2.58 (0.80, 9.44). As expected, VDZ IV had similar maintenance efficacy and safety outcomes relative to VDZ SC. CONCLUSION(S): Results from this indirect treatment comparison suggest that VDZ SC may achieve higher rates of maintenance response and remission among responders at start of maintenance than ADA and is associated with a lower risk of overall AEs. In the absence of a head-to-head trial between VDZ SC and ADA SC, these findings support a favorable benefit-risk profile of VDZ SC in UC.

Efficacy of Pomalidomide, Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma Post-Lenalidomide: Results from a Systematic Literature Review and Indirect Treatment Comparison

IntroductionThe efficacy of sarilumab and upadacitinib, in combination with disease-modifying antirheumatic drugs (DMARDs), was demonstrated in phase 3 clinical trials of patients with rheumatoid arthritis (RA) refractive to previous biologic DMARDs. In the absence of head-to-head clinical trials, the matching-adjusted indirect comparison (MAIC) and simulated treatment comparison (STC) estimate the relative efficacy of sarilumab and upadacitinib in patients with RA who had an inadequate response to previous biologic DMARDs.MethodsPatient-level data for sarilumab were obtained from the TARGET trial (NCT01709578) and published aggregate data for upadacitinib were obtained from the SELECT-BEYOND trial (NCT02706847). For the MAIC, individual patient data from the TARGET trial were assigned weights such that weighted mean baseline characteristics of the treatment effect modifiers matched those from SELECT-BEYOND. For the STC, the TARGET patient-level data and mean baseline values from SELECT-BEYOND were used to simulate sarilumab treatment effects for a SELECT-BEYOND population. Endpoints evaluated included the American College of Rheumatology (ACR) response criteria ACR20/50/70, Disease Activity Score-28 for Rheumatoid Arthritis with C-reactive protein (DAS28-CRP) < 3.2, DAS28-CRP < 2.6, Simple Disease Activity Index (SDAI) < 3.3, and Clinical Disease Activity Index (CDAI) < 2.8 at 12 weeks.ResultsThe analysis included 365 patients from TARGET and aggregated data of 333 patients from SELECT-BEYOND. Matching for potential treatment effect baseline modifiers (i.e., age, oral glucocorticoid use, tender joint count of 68 counts, swollen joint count of 66 counts, serum CRP level, and patient global assessment of disease activity) resulted in a reduction of the effective sample size of TARGET population to 166. Following MAIC and STC analysis, the odds of achieving all aforementioned clinical outcomes versus placebo at week 12 were similar for sarilumab and upadacitinib.ConclusionIn the MAIC and STC analyses from TARGET and SELECT-BEYOND trials, the efficacy of sarilumab and upadacitinib were comparable.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-022-00521-1.

Interpreting Indirect Treatment Comparisons and Network Meta-Analysis for Health-Care Decision Making: Report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices: Part 1

The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials

A systematic review and indirect treatment comparison of perampanel versus brivaracetam as adjunctive therapy in patients with focal-onset seizures with or without secondary generalization

Introduction Neurofibromatosis type 1 (NF1) is a rare genetic disorder frequently complicated by plexiform neurofibromas (PNs) – benign but often morbid tumors associated with pain, disfigurement, and functional impairment. Mitogen-activated protein kinase (MEK) inhibitors have emerged as an approach for the management of NF1-PNs. Areas covered This review summarizes the pharmacology, mechanism of action, preclinical rationale, and clinical development of mirdametinib, a selective MEK1/2 inhibitor approved for the treatment of symptomatic, inoperable NF1-PNs in children and adults. We review key pharmacokinetic and pharmacodynamic properties, preclinical data supporting MAPK/ERK pathway inhibition, and outcomes from mirdametinib clinical trials. Emphasis is placed on efficacy outcomes, patient-reported benefits, durability of response, safety profile, and regulatory milestones. Emerging evidence from indirect treatment comparisons and early combination strategies is also discussed to contextualize mirdametinib within the evolving therapeutic landscape. Expert opinion Mirdametinib represents a meaningful advance in the management of NF1-PNs, offering durable tumor volume reduction, improvements in pain and quality of life, and a manageable safety profile across age groups. While head-to-head comparisons with other MEK inhibitors are lacking, available evidence suggests a favorable balance of efficacy and tolerability that may support its use as a first-line systemic option in appropriately selected patients.

Beginning in January 2025, all new active substances must undergo evaluation of relative clinical effectiveness through European Union (EU) joint clinical assessments (JCAs). In the absence of head-to-head data, indirect treatment comparisons (ITCs) become indispensable in meeting the numerous population, intervention, comparators and outcomes (PICO) criteria to support decision-making. This study examined ITCs in European Network for Health Technology Assessment (EUnetHTA) relative effectiveness assessments (REAs) to obtain valuable insights into their potential implications for future JCAs. The EUnetHTA website was hand-searched for REAs of pharmaceutical products between 2010 and 2021. Information on PICO, ITC methods, ITC limitations/critiques, and relative effectiveness conclusions were systematically extracted. On the basis of the final EUnetHTA critiques, suitability of ITC evidence was categorised by the current study authors as appropriate, unsuitable or unclear. Twenty-three REAs were identified. Twelve REAs included an ITC, of which six were in oncology indications. Across the REAs, 64 comparisons were required, with a median of four comparators per REA (range 1-18). In total, 25 comparisons were informed by indirect evidence; the suitability of ITCs was categorised as unclear in all but one of the 25 comparisons. Multiple analyses and ITCs were necessary to address multiple PICOs. Although most ITCs were categorised as unclear within the REAs, they were still considered appropriate to inform decision-making. The EU JCA process will most likely require health technology developers to use various ITC approaches to address the multiple PICOs requested, recognising the inherent limitations of these methodologies. Efforts to address potential challenges for EU JCA should focus on supporting JCA assessors/co-assessors and national HTA agencies in the evaluation and interpretation of ITCs to enable decision-making.

Background: Chimeric antigen receptor T-cell (CAR-T) therapies have been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of diffuse large B-cell lymphoma (DLBCL), primarily based on single-arm trials or indirect comparisons with stem cell transplantation. However, no direct head-to-head comparisons of CAR-T therapies have been conducted, largely due to their high cost. To assess their true value, indirect treatment comparisons (ITCs) are essential. These comparisons, however, are prone to confounding biases, which necessitate careful adjustments through the identification and measurement of relevant variables. Materials and Methods: This study aims to identify the variables used for adjustment in ITCs of CAR-T therapies for DLBCL and examine the methodologies employed to select them. A rapid literature review was conducted in PubMed in September 2023, focusing on ITCs involving CAR-T therapies for DLBCL. The search was based on keywords categorized into three groups: techniques (ITCs and related terms), drugs (CAR-T therapies), and indication (DLBCL). Results: The rapid literature review identified 21 articles, of which 11 were selected for analysis. Exclusions were made for articles that did not identify confounders, were letters to editors, or addressed conditions other than DLBCL. Among the 11 selected publications, 10 did not clearly specify the methodology used to identify adjustment variables. A total of 25 potential confounders were identified across the studies, with substantial variability in the set of variables used, reflecting a lack of standardization in confounder selection. Commonly identified confounders included the number of prior treatment lines and Eastern Cooperative Oncology Group Performance Status (ECOG PS), although their inclusion as adjustment variables in ITCs was inconsistent, often due to missing data. Conclusions: While the identified confounders are clinically relevant, the methodologies for selecting them remain unclear, resulting in significant variability across studies. Additionally, key variables commonly considered in health technology assessments (HTAs), such as age, sex, and disease severity, were inconsistently incorporated into ITCs. To improve the reliability and consistency of ITC outcomes, there is a pressing need for standardized methodologies for identifying and adjusting for confounders.

Psoriasis is a chronic skin disease for which there is an increasing range of treatment options. Biological agents (ustekinumab, adalimumab, infliximab and etanercept) are indicated for moderate-to-severe plaque-type psoriasis in adults who fail to respond to, have a contraindication to, or are intolerant to other systemic therapies including cyclosporine, methotrexate and PUVA Unfortunately, with new drugs, the pivotal trials leading to their licensing are often placebo-controlled trials rather than comparative trials vs. established therapies. Therefore, inference on comparative effectiveness of the newer agents must be derived indirectly, through estimation of effects of the new agents vs. a common comparator. The objective of this study is to compare the relative efficacy of the biological agents through a systematic review of the indirect clinical trial evidence. A systematic literature search was performed for clinical trials of biological agents in psoriasis. Pivotal, randomized, double-blind, controlled (placebo) trials using intention-to-treat analysis were selected for detailed analysis. Trials must include PASI 75 as a primary end point. The indirect comparison was performed using the method of Bucher adjusted with the ITC calculator (Indirect Treatment Comparisons of the Canadian Agency for Drugs and Technologies in Health), etanercept being the reference drug. We defined delta value for therapeutic equivalence as a difference in the efficacy of 25% among the different treatment options. Fourteen studies (four for ustekinumab, three for adalimumab, three for infliximab and four for etanercept) were included. The indirect comparison results reveal that ustekinumab, adalimumab and infliximab were statistically superior to etanercept with an absolute risk difference for PASI 75 of 12% (95% CI=5·9-18%), 11% (95% CI=5·3-16·7%) and 24% (29·7-18·3%) respectively. However, in all situations, the 95% confidence interval does not achieve clinical relevance as no delta exceeds the previously set value (25%). Ustekinumab, adalimumab, infliximab and etanercept can be regarded as clinical equivalents for the treatment of psoriasis. Choice between these agents therefore depends on their relative safety profiles, individual contra-indications and cost effectiveness.

Efficacy of Subcutaneous Epcoritamab Vs Tisa-Cel in R/R LBCL CAR T-Naive and CAR T-Eligible Patients: An Indirect Comparison

Although systemic corticosteroids (SCS) have long been used to treat patients with COPD exacerbation, the recommended dose remains controversial. We aimed to perform a meta-analysis and an indirect treatment comparison to investigate the efficacy and safety of different doses of SCS in subjects with COPD exacerbation. Studies were identified by searching different databases for randomized controlled trials that investigated the efficacy and safety of SCS with placebo in subjects with exacerbation of COPD. The different doses of SCS were assigned to low-dose (ie, initial dose ≤ 40 mg prednisone equivalent/d [PE/d]), medium-dose (initial dose = 40-100 mg PE/d, and high-dose (initial dose > 100 mg PE/d) groups. The indirect treatment comparison was performed between low-, medium-, and high-dose SCS groups. Twelve trials with 1,375 participates were included. Compared to placebo, the risk of treatment failure was lower in the low-dose SCS groups (risk ratio 0.61 [95% CI 0.43-0.88], P = .007) and high-dose SCS groups (risk ratio 0.64 [95% CI 0.48-0.85], P = .002); the FEV1 was significantly improved in low-dose (mean difference 0.09 [95% CI 0.06-0.12], P < .001), medium-dose (mean difference 0.23 [95% CI 0.02-0.44], P = .036), and high-dose SCS groups (mean difference 0.09, [95% CI 0.03-0.15], P < .001, respectively). Regarding safety, the incidence of hyperglycemia was higher in high-dose SCS groups versus placebo (risk ratio 2.52 [95% CI 1.13-5.62], P = .02). The indirect comparison between low-, medium-, and high-dose SCS found that the risk of treatment failure and changes in FEV1 were similar between these doses of SCS. This meta-analysis indicates that low-dose SCS (initial dose ≤ 40 mg PE/d) was sufficient and safer for treating subjects with COPD exacerbation, and it was noninferior to higher doses of SCS (initial dose > 40 mg PE/d) in improving FEV1 and reducing the risk of treatment failure. However, our findings need to be verified in head-to-head randomized controlled trials.

BackgroundThere are no head-to-head clinical studies comparing chimeric antigen receptor (CAR) T-cell therapies for the treatment of relapsed or refractory aggressive large B-cell lymphomas. Naive, indirect comparisons may be inappropriate, as the study designs and patient populations could differ substantially. Matching-adjusted indirect comparisons (MAIC) can reduce many biases associated with indirect comparisons between studies. To determine the comparative efficacy and safety of lisocabtagene maraleucel (liso-cel) to tisagenlecleucel, we describe an unanchored MAIC of the pivotal studies TRANSCEND NHL 001 (TRANSCEND; NCT02631044; liso-cel) and JULIET (NCT02445248; tisagenlecleucel).MethodsIndividual patient data (IPD) from TRANSCEND were available to the authors; for the JULIET pivotal study, summary-level data from the published study were used. To balance the populations between two studies, IPD from TRANSCEND were adjusted to match the marginal distribution (e.g., mean, variance) of clinical factors among patients from JULIET.ResultsResults from the primary MAIC showed liso-cel had statistically significant greater efficacy than tisagenlecleucel (objective response rate: odds ratio [OR] = 2.78, 95% confidence interval [CI]: 1.63‒4.74; complete response rate: OR = 2.01, 95% CI: 1.22‒3.30; progression-free survival: hazard ratio [HR] = 0.65, 95% CI: 0.47‒0.91; overall survival: HR = 0.67, 95% CI: 0.47‒0.95). MAIC of safety outcomes showed lower ORs for all-grade and grade ≥ 3 cytokine release syndrome, and grade ≥ 3 prolonged cytopenia for liso-cel when compared with tisagenlecleucel; there were no statistically significant differences detected for other safety outcomes.ConclusionsOverall, this MAIC of two CAR T-cell therapies indicates liso-cel had favorable efficacy and a comparable or better safety profile relative to tisagenlecleucel.Clinical trial registration: ClinicalTrials.gov identifiers: NCT02631044 and NCT02445248.

Indirect treatment comparison of nivolumab versus placebo for the adjuvant treatment of melanoma

AimTo compare the effects of semaglutide 1.0 mg versus dulaglutide 3.0 and 4.5 mg on HbA1c and body weight in patients with type 2 diabetes.Materials and MethodsA Bucher indirect comparison was conducted to compare efficacy outcomes of semaglutide 1.0 mg versus dulaglutide 3.0 and 4.5 mg using published results from the SUSTAIN 7 and AWARD‐11 trials. Sensitivity analyses using individual patient data from SUSTAIN 7 and aggregate data from AWARD‐11 were conducted to explore the impact of adjustment for cross‐trial imbalances in baseline characteristics.ResultsSemaglutide 1.0 mg significantly reduced HbA1c versus dulaglutide 3.0 mg, with an estimated treatment difference (ETD) of −0.24%‐points (95% confidence interval [CI] −0.43, −0.05), with comparable reductions in HbA1c versus dulaglutide 4.5 mg with an ETD of −0.07%‐points (95% CI −0.26, 0.12). Semaglutide 1.0 mg significantly reduced body weight versus dulaglutide 3.0 and 4.5 mg with an ETD of −2.65 kg (95% CI −3.57, −1.73) and −1.95 kg (95% CI −2.87, −1.03), respectively. Sensitivity analyses supported the primary analysis findings.ConclusionsThis indirect comparison showed significantly greater reductions in HbA1c with semaglutide 1.0 mg versus dulaglutide 3.0 mg and comparable HbA1c reductions versus dulaglutide 4.5 mg. Semaglutide 1.0 mg significantly reduced body weight versus both dulaglutide 3.0 and 4.5 mg. With several glucagon‐like peptide‐1 receptor agonists available, information regarding their comparative efficacy can be valuable to clinicians.