Matching-adjusted Indirect Comparison Analyses Research Articles

A matching-adjusted indirect comparison of results from REDUCE and RESPECT—two randomized trials on patent foramen ovale closure devices to prevent recurrent cryptogenic stroke

Aims Two randomized clinical trials, REDUCE and RESPECT, demonstrated that patent foramen ovale (PFO) closure in combination with antithrombotic therapy was more effective for the prevention of recurrent ischemic stroke compared with antithrombotic therapy alone. The aim of this study was to determine the relative efficacy and safety of the PFO closure devices used in REDUCE (HELEX and CARDIOFORM Septal Occluders) compared with the device used in RESPECT (Amplatzer PFO Occluder). Methods An unanchored matching-adjusted indirect comparison (MAIC) of the PFO closure arms of the REDUCE and RESPECT trials was performed using patient-level data from REDUCE weighted to match baseline characteristics from RESPECT. Comparisons of the following outcomes were made between the devices assessed in the trials: risk of recurrent ischemic stroke; recurrent ischemic stroke one year after randomization; any serious adverse event (SAE) related to the procedure or device; and atrial fibrillation or atrial flutter as an SAE related to the procedure or device. Results After conducting the MAIC, baseline characteristics were well-matched between the two trials. Compared to RESPECT, PFO closure using the devices from REDUCE resulted in a hazard ratio of 0.46 (95% confidence interval [CI] 0.15–1.43; p = 0.17) for the risk of recurrent stroke. For the recurrence of stroke after one year, SAE related to the procedure or device, and atrial fibrillation or atrial flutter as SAE related to the procedure or device, the MAIC resulted in a rate difference of −0.68 (95%CI −2.06 to 0.70; p = .34), −1.29 (95%CI −3.82 to 1.25; p = .32), and −0.19 (95%CI −1.16 to 0.78; p = .71), respectively. These findings were consistent across scenario analyses. Conclusions This MAIC analysis found no statistically significant differences in efficacy and safety outcomes between PFO closure with the HELEX and CARDIOFORM Septal Occluders versus the Amplatzer PFO Occluder, as used in the REDUCE and RESPECT trials.

Comparative efficacy, quality of life, safety, and tolerability of atogepant and rimegepant in migraine prevention: A matching-adjusted indirect comparison analysis.

Comparative evaluations of preventive migraine treatments can help inform clinical decision making for managing migraine in clinical practice. An anchored matching-adjusted indirect comparison analysis was conducted using pooled participant-level data from two phase 3 atogepant trials (ADVANCE and PROGRESS) and one phase 2/3 rimegepant trial (BHV3000-305) to evaluate the relative efficacy and safety/tolerability of atogepant and rimegepant as preventive migraine treatments. Participants receiving atogepant 60 mg once daily, rimegepant orally disintegrating tablet 75 mg once every other day, and placebo were included. Only participants meeting the BHV3000-305 inclusion/exclusion criteria were analyzed: ≥6 monthly migraine days and ≤18 monthly headache days at baseline. The primary efficacy assessment of interest was change in monthly migraine days across weeks 1-12. There were 252 participants in the atogepant group and 348 in the rimegepant group. Across weeks 1-12, atogepant 60 mg demonstrated a significantly greater reduction in mean monthly migraine days compared with rimegepant 75 mg (mean difference [95% CI]: -1.65 [-2.49, -0.81]; p < 0.001). Both atogepant and rimegepant demonstrated similar safety/tolerability profiles. In this matching-adjusted indirect comparison analysis, oral atogepant 60 mg once daily demonstrated a significantly greater reduction in monthly migraine days compared with rimegepant 75 mg orally disintegrating tablet once every other day.

A matching-adjusted indirect comparison of the efficacy of elranatamab versus physician’s choice of treatment in patients with triple-class exposed/refractory multiple myeloma

Introduction For patients with triple-class exposed/refractory multiple myeloma (TCE/R MM), prognosis is poor and effective treatment options are limited. Elranatamab is a novel B-cell maturation antigen (BCMA)- and CD3-directed bispecific antibody which was approved by the US Food and Drug Administration in August 2023 and demonstrated safety and efficacy in patients with TCE/R MM in the phase 2, single-arm MagnetisMM-3 trial (NCT04649359). To compare the effectiveness of elranatamab vs physician’s choice of treatment (PCT) in the absence of head-to-head comparative data, a matching-adjusted indirect comparison (MAIC) was conducted. Methods Individual patient data from MagnetisMM-3 (Cohort A [BCMA-naïve] N = 123, 14.7 months of follow-up) were reweighted to match published summary data from two real-world studies of PCT in patients with TCE/R MM (LocoMMotion and MAMMOTH) using a propensity score-type logistic regression. Unanchored MAIC analyses were conducted according to National Institute for Health and Care Excellence (NICE) Decision Support Unit (DSU) 18 guidance. Results Compared with PCT in LocoMMotion, elranatamab was associated with a significantly higher objective response rate (ORR rate difference: 37.52; 95% CI 26.20–48.83; odds ratio: 4.85; 95% CI 2.85–8.23) and complete or stringent complete response rate (≥CR rate difference: 42.29; 95% CI 31.84–52.74; odds ratio: 184.01; 95% CI 24.66–1372.86), longer progression-free survival (PFS HR 0.32; 95% CI 0.20–0.49), and overall survival (OS HR 0.62; 95% CI 0.40–0.94). Compared with PCT in MAMMOTH, elranatamab was associated with significantly higher ORR (rate difference: 28.14; 95% CI 16.77–39.52; odds ratio: 3.24; 95% CI 1.98–5.32) and ≥ CR (rate difference: 26.22; 95% CI 16.40–36.05; odds ratio: 5.48; 95% CI 2.88–10.44), as well as longer PFS (HR 0.25; 95% CI 0.17–0.37) and OS (HR 0.49; 95% CI 0.33–0.71). Sensitivity analysis results were consistent with the base case. Conclusion In the MAIC, elranatamab was consistently associated with improved rates and depth of response and significantly longer PFS and OS versus PCT in LocoMMotion and MAMMOTH.

Matching-Adjusted Indirect Comparison of Personalized Prophylaxis with Simoctocog Alfa Versus Standard Prophylaxis with Efanesoctocog Alfa in Adults with Severe Hemophilia a

Background: Personalized factor VIII (FVIII) prophylaxis is currently the gold standard approach for the treatment of patients with severe hemophilia A. Although several FVIII concentrates are available, head-to-head comparative studies of their relative efficacy are not feasible in rare diseases such as hemophilia A. In such situation, the use of validated indirect comparison methods such as matching-adjusted indirect comparison (MAIC) methodology can be used to indirectly compare outcomes from separate clinical studies. MAIC can be used to adjust for differences in patient characteristics between studies, with the goal to reduce bias in the treatment effect estimates which can occur with comparison of efficacy data across clinical trials. Aims: To indirectly compare the efficacy of a pharmacokinetic (PK)-guided personalized prophylaxis regimen with simoctocog alfa (Nuwiq ®; a 4 th-generation recombinant FVIII [rFVIII] concentrate with no chemical modifications of fusion proteins) against a standard prophylaxis regimen with efanesoctocog alfa (Altuviiio ®; an Fc-fusion rFVIII concentrate with chemical modifications including Von Willebrand factor independent-XTEN fusion protein), in previously-treated patients (PTPs) with severe hemophilia A. Methods: After matching study populations by accounting for clinically important baseline characteristics,individual patient-level data (IPD) from 65 patients treated with simoctocog alfa from the NuPreviq study were compared against aggregate data from the once-weekly efanesoctocog alfa arm of the XTEND-1 study (n=133). All patients enrolled in both studies were male, with the exception of one female in XTEND-1. Baseline age and body weight were used to re-weight the simoctocog alfa IPD to match the aggregate data reported for efanesoctocog alfa from the XTEND-1 study. Unanchored indirect treatment comparisons were performed for various clinical outcomes using the re-weighted data for simoctocog alfa and the published comparator study data. The endpoints analysed were annualized bleeding rates (ABRs), percentage of patients with zero bleeds, and weekly consumption of FVIII. All efficacy endpoints reported here consider treated and untreated bleeds. Results: After matching populations, the effective sample size for simoctocog alfa was 35.3. Although, the percentage of patients with zero bleeds was higher with simoctocog alfa versus efanesoctocog alfa (64.1% vs 55.5%), this difference was not statistically significant (Table 1). The mean total ABRs were similar between the two products: 1.5 for simoctocog alfa and 1.1 for efanesoctocog alfa (Table 1). The mean weekly dose was significantly higher in patients treated with simoctocog alfa versus efanesoctocog alfa (98.3 IU/kg vs 52.2 IU/kg, respectively; p&amp;lt;0.0001). Conclusion: An indirect comparison analysis demonstrated that a PK-guided, personalized prophylaxis with simoctocog alfa in adult PTPs resulted in zero bleed rates and ABRs that are not statistically different from those with efanesoctocog alfa. The higher total weekly dose observed with simoctocog alfa is to be expected based on the dosing recommendations for each respective FVIII replacement product. This MAIC analysis provides important comparative efficacy and utilization data, which can help guide patients and physicians in making decisions regarding product choice for prophylaxis regimens.

A Matching-Adjusted Indirect Comparison of the Efficacy of Elranatamab Versus Physician's Choice of Treatment in Patients with Triple-Class Exposed/Refractory Multiple Myeloma

BACKGROUND For patients with triple-class exposed/refractory multiple myeloma (TCE/R MM), prognosis is poor and limited effective treatment options are available. Elranatamab is a novel B-cell maturation antigen (BCMA)- and CD3-directed bispecific antibody that demonstrated safety and efficacy in patients with TCE/R MM in the phase 2, single-arm MagnetisMM-3 trial (NCT04649359). To compare the effectiveness of elranatamab vs physician's choice of treatment (PCT) in the absence of comparative data, an unanchored matching-adjusted indirect comparison (MAIC) was conducted. METHODS Individual patient data (IPD) from the 14.7-month follow-up of MagnetisMM-3 (Cohort A [BCMA-naïve] N=123) was matched to published summary data from two real-world studies of PCT: LocoMMotion ([NCT04035226]), an ongoing, prospective, non-interventional study of PCT in patients with TCE MM (N=248); and MAMMOTH, a multicenter, retrospective study investigating the history and outcomes of patients with TCE MM who received subsequent therapies (N=177). To adjust for differences in baseline characteristics, patients from MagnetisMM-3 were reweighted to match those in LocoMMotion reported in Mateos et al (2022) and MAMMOTH reported in Bal et al (2022). The base-case adjustment variables were selected based on univariate Cox regressions using the MagnetisMM-3 IPD, a systematic literature review of prognostic variables and effect modifiers in RRMM, a review of the prognostic variables identified in clinical studies for TCE/R MM, a review of the recent analogous indirect comparisons, and confirmation by clinical experts. Weights were determined using a propensity score-type logistic regression via the method of moments (Signorovitch et al. 2012) based on age, median time since diagnosis, International Staging System disease stage, high-risk cytogenetics, extramedullary disease, number of prior lines of therapy, Eastern Cooperative Oncology Group performance status, creatinine clearance, and penta-exposed and penta-refractory status (where available). In the analysis for the endpoint of overall survival (OS), sex was also included in the analysis. A sensitivity analysis was conducted in which missing values of the adjusted baseline characteristics for elranatamab were imputed by a random sample of the observations in MagnetisMM-3 to potentially increase the effective sample size (ESS). Unanchored MAIC analyses used the R Studio statistical code provided in the National Institute for Health and Care Excellence Decision Support Unit 18 by Phillippo et al (2016) . In the MAIC vs LocoMMotion &amp; MAMMOTH, adjusted objective response rate (ORR), complete response rate or better (≥CR), progression-free survival (PFS), and OS at 15 months for elranatamab were compared with PCT. Results were reported as rate differences, which is the difference between the ORR or ≥CR rates of elranatamab and PCT, and odds ratios (ORs) for binary endpoints and hazard ratios (HRs) for time-to-event endpoints, with two-sided 95% confidence intervals (CIs). RESULTS In the MAIC for elranatamab vs PCT in LocoMMotion, the post-matching ESS was 68 for all endpoints in the base case. Compared with PCT in LocoMMotion, elranatamab was associated with a significantly higher ORR (rate difference: 37.52; 95% CI 26.20-48.83; OR: 4.85; 95% CI 2.85-8.23), higher ≥CR (rate difference: 42.29; 95% CI 31.84-52.74; OR: 184.01; 95% CI 24.66-1372.86), and longer PFS (HR 0.32; 95% CI 0.20-0.49) and OS (HR 0.62; 95% CI 0.40-0.94) (Table 1). In the MAIC vs PCT in MAMMOTH, the base-case post-matching ESSs were 100 for all endpoints. Compared with PCT in MAMMOTH, elranatamab was associated with a significantly higher ORR (rate difference: 28.14; 95% CI 16.77-39.52; OR: 3.24; 95% CI 1.98-5.32) and ≥CR (rate difference: 26.22; 95% CI 16.40-36.05; OR: 5.48; 95% CI 2.88-10.44). Elranatamab also had longer PFS (HR 0.25; 95% CI 0.17-0.37) and OS (HR 0.49; 95% CI 0.33-0.71) than PCT (Table 2). Sensitivity analysis results were consistent with the base case. CONCLUSIONS In this MAIC, elranatamab demonstrated significantly higher ORR, higher ≥CR rate, longer PFS, and longer OS compared with PCT in the real-world. These results suggest that elranatamab offers significantly improved outcomes versus standard treatments used in patients with TCE/R MM in clinical practice.

A Matching-Adjusted Indirect Comparison of the Efficacy of Elranatamab Versus Physician's Choice of Treatment Among Patients with Triple-Class Exposed/Refractory Multiple Myeloma in Canada

BACKGROUND Given the poor prognosis and limited treatment options for patients with triple-class exposed/refractory multiple myeloma (TCE/R MM), there is a strong unmet need for novel interventions. Elranatamab, a B-cell maturation antigen (BCMA)- and CD3-directed bispecific antibody, recently demonstrated efficacy and safety in patients with TCE/R MM in the phase 2, single-arm MagnetisMM-3 trial (NCT04649359). The effectiveness of elranatamab was compared with physician's choice of treatment (PCT) in Canada through an unanchored matching-adjusted indirect comparison (MAIC), due to the absence of mature head-to-head comparative trial data. METHODS Individual patient data (IPD) from 14.7-month follow-up of MagnetisMM-3 (Cohort A [BCMA- naïve] N=123) was weighted to match published summary data from Canadian Myeloma Research Group (CMRG) database, which reported treatment patterns and outcomes on real-world patients with TCE/R MM in Canada (N = 199). Only BCMA-naïve patients from the MagnetisMM-3 trials were considered as BCMA therapies are not currently available as standard of care treatment options in Canada. To adjust for differences in baseline characteristics, patients from MagnetisMM-3 were reweighted to match those reported in the CRMG database. The adjustment variables were selected based on univariate Cox regressions using the MagnetisMM-3 IPD, a systematic literature review of prognostic variables and effect modifiers in relapsed or refractory MM, and a review of the recent analogous indirect comparisons, and confirmation by clinical experts. Weights were determined using a propensity score-type logistic regression via the method of moments (Signorovitch et al. 2012), based on age, median time since diagnosis, and number of prior lines of therapy. In the analysis for the endpoint of overall survival (OS), sex was also included in the analysis. A limitation of this MAIC is that key prognostic variables, such as International Staging System disease stage, cytogenetic risk, and extramedullary disease, were not adjusted for in the analysis as the definitions were not comparable between the data sources. Unanchored MAIC analyses used R code provided in the National Institute for Health and Care Excellence (NICE) Decision Support Unit (DSU) 18 by Phillippo et al (2016). The respective outcomes in the MAIC were OS and progression-free survival (PFS) based on the 15-month follow-up data for elranatamab. Results were reported as hazard ratios (HRs) for time-to-event endpoints, with 95% confidence intervals (CIs). RESULTS Median PFS and OS was not reached in the MagnetisMM-3 trial. Patients with TCE/RMM treated with PCT had a median PFS of 4.4 months (95% CI 3.6 - 5.3) and a median OS of 10.5 months (95% CI 8.5 - 13.8). Following weighting, the summary statistics of key baseline characteristics were matched between elranatamab and CMRG. The effective sample size was 82 post-matching for PFS and 81 post-matching for OS. Compared with the patients in the CMRG database, elranatamab was associated with better PFS (HR: 0.36; 95% CI 0.23 - 0.54) and better OS (HR: 0.48; 95% CI 0.32 - 0.73). CONCLUSIONS In this MAIC, among TCE/R MM patients elranatamab demonstrated a significantly longer OS and PFS compared with PCT in the real-world setting reported in the CMRG database.

Updated Results from a Matching-Adjusted Indirect Comparison of Efficacy Outcomes for Isatuximab Plus Pomalidomide and Dexamethasone Versus Daratumumab Plus Pomalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma

Introduction: Findings from a previously conducted matching-adjusted indirect comparison (MAIC) between isatuximab plus pomalidomide and dexamethasone (IsaPd) and daratumumab plus pomalidomide and dexamethasone (DaraPd) among relapsed and/or refractory multiple myeloma (RRMM) patients receiving at least two prior lines of therapy (LoT) including lenalidomide and a proteasome inhibitor (PI) demonstrated a significantly better overall survival (OS) and a positive trend for progression-free survival (PFS), overall response rate (ORR), and very good partial response or better (≥VGPR) rates with IsaPd than that with DaraPd, with a similar safety profile for both treatments [Leleu X et al, Value in Health 2022;25(1):S39]. The present study used longer follow-up data from the phase 3 ICARIA trial (NCT02990338) to update the previous MAIC, evaluating the comparative efficacy of IsaPd versus DaraPd. Methods: A MAIC was performed with the latest available individual patient-level data (IPD) from the ICARIA trial (IsaPd arm, n = 154; Pd arm, n = 153), data cutoff of March 14, 2022, and aggregate data from study publications of the phase 3 APOLLO trial (DaraPd arm, n = 151; Pd arm, n = 153, NCT03180736) [Dimopoulos MA, et al. Blood 2022;140 (Suppl 1):7272-7274; Dimopoulos MA, et al. Lancet Oncol. 2021;22(6):801-812; Dimopoulos MA, et al. Blood 2020;136(Suppl 1):5-6]. To match patients with APOLLO, patients in ICARIA who did not meet the inclusion criteria of APOLLO were excluded. In APOLLO, 11% patients received only one prior LoT. As patients with one prior LoT were not enrolled in ICARIA, it was not feasible to match on this factor; however, the treatment effect of DaraPd versus Pd on PFS among these patients was similar to patients in APOLLO with ≥2 prior LoTs. Therefore, this difference in study populations is unlikely to bias the MAIC. Remaining patients in ICARIA were then weighted using standardized MAIC weights (mean value = 1.0) generated using the method of moments, with active treatment and control arms matched separately to ensure any residual imbalances between active and control arms in APOLLO were replicated in the matched ICARIA sample. Anchored MAICs for the hazard ratio (HR) for OS and PFS, odds ratio (OR) for ORR, and ≥VGPR for IsaPd versus DaraPd were calculated using the Bucher method [Bucher HC, et al. J Clin Epidemiol. 1997;50(6):683-691]. Results: MAIC weighting was able to match all characteristics included in the matching algorithm, with standardized mean difference (SMDs) &amp;lt;0.0001 after weighting. The effective sample size after weighting was 28.1 for IsaPd and 43.1 for Pd. Based on an anchored MAIC, OS was significantly better with IsaPd versus DaraPd (HR [95% CI]: 0.49 [0.24-0.98]; p = 0.04) (Figure 1). A numerical trend in favor of IsaPd versus DaraPd was observed for PFS, ORR, and ≥VGPR, although the differences were statistically non-significant (Table 1). Conclusions: This MAIC analysis demonstrated a significant benefit in OS and a positive trend in the improvement of PFS, ORR, and ≥VGPR in favor of IsaPd compared with DaraPd. These findings were consistent with the previous MAIC with a longer follow-up data (present analysis used a maximum follow-up of 4.5 years of OS data from both trials, whereas the previous analysis used a follow-up of 3 years from ICARIA and unknown from APOLLO), which highlights the therapeutic potential of IsaPd in RRMM, particularly for patients who become refractory to lenalidomide and a PI.

A Matching-Adjusted Indirect Comparison of the Efficacy of Elranatamab and Teclistamab in Patients with Triple-Class Exposed/Refractory Multiple Myeloma

BACKGROUND Elranatamab, a novel B-cell maturation antigen (BCMA)- and CD3-directed bispecific antibody, recently demonstrated efficacy and safety in patients with triple-class exposed/refractory multiple myeloma (TCE/R MM) in the phase 2, single-arm MagnetisMM-3 trial (NCT04649359). Teclistamab (TEC) is a BCMA-CD3 directed bispecific antibody which was recently approved in the US for patients with TCE/R MM who received 4+ prior lines of treatment, based on response rates in the MajecTEC-1 trial (NCT04557098). In the absence of comparative trials of elranatamab and TEC, an unanchored matching-adjusted indirect comparison (MAIC) was conducted to assess their relative efficacy. METHODS Individual patient data (IPD) from the 14.7 month follow- up of MagnetisMM-3 Cohort A (BCMA-naïve, N = 123), were reweighted to match published summary data from ~23 month follow-up in MajesTEC-1 (N=165) in Sidana et al (2023). Overall, the inclusion and exclusion criteria of the trials were similar; however, MajesTEC-1 excluded patients with Eastern Cooperative Oncology Group (ECOG) performance status &amp;gt;1; therefore, patients with ECOG 2 in the MagnetisMM-3 trial were removed from the analysis (resulting N=116). To adjust for cross-trial differences, patients from MagnetisMM-3 were reweighted to match the baseline characteristics of the TEC trial patients. Weights were determined using a propensity score-type logistic regression via the method of moments (Signorovitch et al. 2012) based on age, median time since diagnosis, International Staging System disease stage, high-risk cytogenetics, extramedullary disease, number of prior lines of therapy, ECOG performance status, and penta-exposed and penta-refractory status. In the analysis for the overall survival (OS) endpoint, sex was also included. The adjusted variables were obtained based on univariate Cox regressions using the MagnetisMM-3 IPD, a systematic literature review of prognostic variables and effect modifiers in relapsed or refractory MM, a review of the prognostic variables identified in clinical studies for TCE/R MM, and a review of the recent relevant indirect comparisons, and were confirmed by clinical experts. A sensitivity analysis was conducted in which missing values of the adjusted baseline characteristics for elranatamab were imputed by a random sample of the observations in MagnetisMM-3 to potentially increase the effective sample size (ESS). Unanchored MAIC analyses were conducted in R studio following the code provided in the National Institute for Health and Care Excellence (NICE) Decision Support Unit (DSU) 18 by Phillippo et al (2016). The efficacy outcomes included objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and OS. Kaplan-Meier curves of DoR, PFS, and OS from MajesTEC-1 were digitized according to Guyot et al (2012). Results were reported as rate difference (i.e., the difference between the ORR of elranatamab and TEC) and odds ratios (ORs) for binary endpoints or hazard ratios (HRs) for time-to-event endpoints, with 95% confidence intervals (CIs). RESULTS After adjustment in the MAIC, the selected key baseline characteristics were comparable between elranatamab and TEC. For all endpoints except OS, the post-matching ESS for elranatamab was 75 in the base case and 89 in the sensitivity analysis. For OS, the ESSs were 73 and 87 for the base case and scenario analyses, respectively. Compared with TEC, elranatamab was associated with significantly better ORR (rate difference: 12.30; 95% CI: 0.70-23.90; OR: 1.79; 95% CI: 1.01-3.19) and PFS (HR 0.59; 95% CI 0.39-0.89). Patients treated with elranatamab had numerically better DoR (HR: 0.64; 95% CI: 0.33-1.23) and OS (HR: 0.66; 95% CI: 0.42-1.03) compared to those who received TEC (Table 1 and 2). Results in the sensitivity analysis were consistent with the base case. CONCLUSIONS In this MAIC, elranatamab demonstrated significantly better ORR and PFS than TEC, and numerically better DOR and OS in both the base case and the sensitivity analysis. These results suggest that elranatamab is an effective option for treating patients with TCE/R MM.

Matching-Adjusted Indirect Comparison between Personalized Prophylaxis with Simoctocog Alfa Versus Standard Prophylaxis with Emicizumab in Adults with Hemophilia a

Background: Personalized prophylaxis with factor VIII (FVIII) concentrates remains the mainstay therapy for patients with severe hemophilia A. The bispecific monoclonal antibody emicizumab, which mimics FVIII function, is also approved for prophylaxis in hemophilia A patients. Head-to-head comparative studies on the relative efficacy of different therapeutic strategies are not feasible in a rare disease such as hemophilia A. In such situations, the use of indirect comparison methods can help to compare relative efficacies. Matching-adjusted indirect comparison (MAIC) is a well-established statistical method to indirectly compare outcomes from separate clinical studies. It can be used to adjust for differences in patient characteristics between studies, with the goal to reduce bias in the treatment effect estimates which can occur with comparison of efficacy data across clinical trials. Aims: To indirectly compare the efficacy of a pharmacokinetics (PK)-guided personalized prophylaxis regimen with a recombinant, fourth generation, FVIII concentrate, simoctocog alfa (Nuwiq ®), against standard prophylaxis with the bispecific monoclonal antibody emicizumab (Hemlibra ®) in patients with hemophilia A using MAIC methodology. Methods: After matching study populations, accounting for clinically important baseline characteristics,individual patient-level data (IPD) from 65 patients treated with simoctocog alfa from the NuPreviq study were compared against aggregate data for emicizumab administered once weekly (Q1W, N=99), every 2 weeks (Q2W, N=35) or every 4 weeks (Q4W, N=41) from the HAVEN 3 and HAVEN 4 studies. All patients enrolled in all studies were male. Baseline patient variables for matching were chosen based on availability, clinical relevance and distribution overlap. Baseline age and body weight were used to re-weight the simoctocog alfa IPD to match the aggregate data reported for the emicizumab studies. Patients were removed from the NuPreviq study population if they did not meet the eligibility criteria for the comparator studies (but none were excluded from this analysis based on this). Unanchored indirect treatment comparisons were performed for various clinical outcomes using the re-weighted data for simoctocog alfa and the published comparator study data. The endpoints analyzed were total annualized bleeding rates (ABRs) and percentage of patients with zero bleeds. All endpoints considered treated and untreated bleeds. Results: No patients were excluded from the NuPreviq study population due to imposing the body weight or age criteria of the HAVEN 3 and 4 studies. After matching populations, the effective sample size for simoctocog alfa was 33.1, 39.8 and 29.1 participants for the Q1W, Q2W and Q4W comparisons, respectively. The percentage of patients with zero bleeds was significantly higher with simoctocog alfa across all 3 comparisons: simoctocog alfa (74.3%) vs emicizumab Q1W (46.5%); simoctocog alfa (70.3%) vs emicizumab Q2W (40.0%), and simoctocog alfa (81.9%) vs emicizumab Q4W (29.3%; Figure 1, Table 1). The total ABRs were significantly lower with simoctocog alfa versus emicizumab Q1W (1.5 vs 2.9) and emicizumab Q4W (1.4 vs 4.5; Table 1). When comparing simoctocog alfa versus emicizumab Q2W, the difference was not statistically significant (1.3 vs 2.6; Table 1). Conclusion: Indirect comparisons demonstrated that PK-guided, personalized prophylaxis with simoctocog alfa can lead to statistically significantly higher zero bleed rates and decreased ABRs compared with standard emicizumab prophylaxis. This MAIC analysis provides important comparative efficacy and utilization data, which can help guide patients and physicians in making decisions regarding product choice for prophylaxis regimens.

Updated Results from a Matching-Adjusted Indirect Comparison of Efficacy Outcomes of Isatuximab Plus Carfilzomib and Dexamethasone Versus Daratumumab Plus Lenalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma

Introduction: Findings from a previously conducted matching-adjusted indirect comparison (MAIC) between isatuximab plus carfilzomib with dexamethasone (IsaKd) and daratumumab plus lenalidomide and dexamethasone (DRd) among relapsed and/or refractory multiple myeloma (RRMM) patients receiving one to three prior lines of therapy (LoT) demonstrated a significantly better progression-free survival (PFS) and a positive trend for overall survival (OS) in favor of IsaKd compared with DRd (median follow up of 20.7 months for IKEMA trial). Additionally, IsaKd demonstrated an acceptable safety profile with significantly lower rates of several treatment-emergent adverse events than DRd [Richter J et al, Cancer Med 2023;12(7):8005-8017; Richter J et al.(Publication Number 1962), 63 rd ASH Annual Meeting and Exposition, 2021; Richter J, et al. P-213, Clin Lymphoma Myeloma Leuk. 2021;21(Suppl 2):S156-S157]. The present study used longer follow-up data from the phase 3 IKEMA trial (NCT03275285) to update the previous MAIC evaluating the comparative efficacy of IsaKd versus DRd. Methods: A MAIC was performed with the latest available individual patient-level data (IPD) from the IKEMA trial (IsaKd arm, n = 179) (data cutoff: February 2023 for OS and January 2022 for PFS), and aggregate data from study publications of phase 3 POLLUX trial (DRd arm, n = 286, NCT02076009) [Bahlis NJ et al. Leukemia 2020;34(7):1875-1884; Dimopoulos MA et al. Hemasphere 2022;6:13]. Patients were selected from the IsaKd arm of the IKEMA trial to match the inclusion and exclusion criteria of the POLLUX trial. Individual patients from the IKEMA trial were then assigned weights such that (1) weighted mean baseline characteristics for patients in the IsaKd arm matched those reported for patients in the DRd arm, and (2) each patient's weight was equal to their estimated odds (propensity) of being in the POLLUX trial versus the IKEMA trial. After matching, outcomes were compared across the two trial populations. For PFS and OS, hazard ratio (HR) and 95% confidence interval (CI) were reported from a Cox proportional hazards (PH) model using the weighted sample for IsaKd and the pseudo-IPD for DRd extracted from published Kaplan-Meier curves via digitization software [Mark M et al, Engauge Digitizer Software; http://markummitchell.github.io/engauge-digitizer]. For any violations of the PH assumption, the restricted mean survival time (RMST) at median follow-up of IKEMA for the outcome of interest was calculated instead. Results: After the MAIC adjustment, all available baseline characteristics were well balanced across the trial populations. For PFS, as the PH assumption was violated ( χ2 = 5.52, p = 0.019), RMST method was used to compare the two treatments. PFS was significantly better with IsaKd versus DRd (mean difference [95% CI]: 3.63 months [0.14-7.12]; p = 0.04) at 44 months follow-up using RMST method. For OS, the PH assumption ( χ2 = 0.89, p =0.35) was not violated. A numeric, statistically non-significant trend in favor of IsaKd versus DRd was observed for OS (Figure 1). Conclusions: This MAIC analysis demonstrated a significant benefit in PFS and a positive trend in the improvement of OS with IsaKd compared with that with DRd. These findings with a longer follow-up were consistent with the previous analyses conducted with a follow-up of 2 years. These data highlight the therapeutic potential of IsaKd, a lenalidomide-free regimen, in RRMM patients receiving one to three prior LoT compared with a lenalidomide-based regimen.

A Matching-Adjusted Indirect Comparison of Acalabrutinib with and without Obinutuzumab Versus Zanubrutinib in Treatment-Naïve Chronic Lymphocytic Leukemia

Introduction The second-generation Bruton tyrosine kinase inhibitors acalabrutinib (acala) and zanubrutinib (zanu) have not been compared with each other in a head-to-head randomized controlled trial (RCT). Acala with and without obinutuzumab (obin) was evaluated in the ELEVATE-TN RCT in treatment-naïve patients with chronic lymphocytic leukemia (CLL). Zanu was evaluated in treatment-naïve patients with CLL/small lymphocytic leukemia (SLL) in cohorts 1 and 2 of the SEQUOIA RCT. We used an unanchored matching-adjusted indirect comparison (MAIC) to compare the efficacy and safety of acala ± obin versus zanu in patients with treatment-naïve CLL/SLL without del(17p). Datasets were derived from comprehensive individual patient data (IPD) from ELEVATE-TN and published aggregate data from cohort 1 in SEQUOIA. Methods In this unanchored MAIC, we weighted IPD for the acala + obin and acala monotherapy arms from ELEVATE-TN to match zanu baseline data from SEQUOIA. We excluded patients with del(17p) in ELEVATE-TN to match cohort 1 in SEQUOIA, which excluded patients with del(17p). Patients were matched based on variables considered prognostic and/or predictive of investigator-assessed progression-free survival (INV-PFS) in an exploratory multivariate Cox-regression analysis of ELEVATE-TN. These were age, ECOG status, Binet stage, bulky disease, B2 microglobulin, cytopenia, del(11q), trisomy 12, IGHV status,and TP53 mutation. The efficacy analysis assessed INV-PFS in randomized patients (acala + obin, n = 162; acala monotherapy, n = 163; zanu, n = 241) using the Oct 2021 data cut-off (DCO) for ELEVATE-TN and the Oct 2022 DCO for SEQUOIA (median follow-up 58 versus 44 months). Pseudo-IPD for INV-PFS for zanu were obtained from Kaplan-Meier curves. The safety analysis assessed the incidence of adverse events (AEs) and reported the odds ratios (ORs) of AEs in treated patients (acala + obin, n = 162; acala monotherapy, n = 162; zanu, n = 240). To compare the incidence of AEs, the ELEVATE-TN Sep 2020 DCO was used to match the median follow-up from the SEQUOIA Oct 2022 DCO (47 versus 44 months). Results In the efficacy analysis, the acala + obin and acala monotherapy effective sample sizes (ESSs) post-matching were 124 (76%) and 105 (64%), respectively. Matching had little impact on acala + obin and acala monotherapy INV-PFS (Figure 1). Post-matching, 36-month INV-PFS was higher with acala + obin (95%; 95% CI: 90-97) than with zanu (84%; 95% CI: 79-88). The MAIC-weighted Cox hazard ratio (HR) found INV-PFS to be superior with acala + obin versus zanu (HR: 0.41; 95% CI: 0.23-0.74; Figure 1). No evidence of a difference between acala monotherapy post-matching and zanu was found when looking at 36-month INV-PFS (86%; 95% CI: 78-91 versus 84%; 95% CI: 79-88; HR: 0.91; 95% CI: 0.53-1.56). In the safety analysis, the acala + obin and acala monotherapy ESSs post-matching were 123 (76%) and 103 (64%), respectively. There were no significant differences in the odds of having most types of AE with acala + obin versus zanu, except for higher odds of having any grade neutropenia (OR: 2.19; 95% CI: 1.33-3.60) and arthralgia (OR: 2.33; 95% CI: 1.37-3.96). Acala monotherapy showed lower odds of having any grade hypertension (OR: 0.44, 95% CI: 0.20-0.99; Figure 2) and no significant differences in the odds of having other types of AEs versus zanu. Conclusions In this MAIC of ELEVATE-TN and SEQUOIA evaluating patients with treatment-naïve CLL/SLL without del(17p), acala + obin had a longer INV-PFS versus zanu, while there was no evidence of a difference between acala monotherapy and zanu. Acala + obin and acala monotherapy generally had similar safety profiles to zanu. However, acala monotherapy was associated with lower odds of any grade hypertension versus zanu, while acala + obin was associated with higher odds of any grade neutropenia and arthralgia versus zanu. Although the results of MAIC analyses can only be hypothesis-generating, these results address an important data gap by systematically comparing these two commonly used regimens where randomized, prospective data are not available.

Mortality risk reduction with budesonide/glycopyrrolate/formoterol fumarate versus fluticasone furoate/umeclidinium/vilanterol in COPD: a matching-adjusted indirect comparison based on ETHOS and IMPACT

ABSTRACT Objective Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. While two approved fixed-dose inhaled corticosteroid/long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) triple therapies reduce all-cause mortality (ACM) versus dual LAMA/LABA therapy in patients with COPD, head-to-head studies have not compared the effects of these therapies on ACM. We compared ACM in adults with moderate-to-very severe COPD receiving budesonide/glycopyrrolate/formoterol fumarate (BGF) in ETHOS versus fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) in IMPACT using a matching-adjusted indirect comparison (MAIC). Methods A systematic literature review identified two studies (ETHOS [NCT02465567]; IMPACT [NCT02164513]) of ≥52 weeks reporting ACM as an efficacy endpoint in patients receiving triple therapy. As ETHOS and IMPACT lack a common comparator, an unanchored MAIC compared ACM between licensed doses of BGF (320/18/9.6 μg) from ETHOS and FF/UMEC/VI (100/62.5/25 μg) from IMPACT in patients with moderate-to-very severe COPD. Using on- and off-treatment data from the final retrieved datasets of the intention-to-treat populations, BGF data were adjusted according to aggregate FF/UMEC/VI data using 11 baseline covariates; a supplementary unadjusted indirect treatment comparison was also conducted. P-values for these post-hoc analyses are not adjusted for Type I error. Results ACM over 52 weeks was statistically significantly reduced by 39% for BGF versus FF/UMEC/VI in the MAIC (hazard ratio [HR] [95% CI]: 0.61 [0.38, 0.95], p = 0.030) and unadjusted analysis (HR [95% CI]: 0.61 [0.41, 0.92], p = 0.019). Conclusion In this MAIC, which adjusted for population heterogeneity between ETHOS and IMPACT, ACM was significantly reduced with BGF versus FF/UMEC/VI in patients with moderate-to-very severe COPD.

Ibrutinib (Ibr) for treatment of relapsed‐refractory (R/R) chronic lymphocytic leukemia (CLL): a matching‐adjusted indirect comparison of 3 randomized phase 3 trials

Introduction: Ibr is a standard therapy for CLL with demonstrated efficacy in first-line and R/R settings. Within R/R CLL, single-agent Ibr was evaluated in 3 randomized phase 3 trials: RESONATE (vs. ofatumumab), ALPINE (vs. zanubrutinib), and ELEVATE-RR (vs acalabrutinib in pts with del(11q) or del(17p)). This analysis evaluated outcomes of Bruton’s tyrosine kinase inhibitor (BTKi) treatment in pts with R/R CLL by comparing the efficacy of Ibr in RESONATE to ALPINE and ELEVATE-RR using a matching-adjusted indirect comparison analysis. Methods: Individual patient data (IPD) of Ibr-treated pts from RESONATE (NCT01578707) were separately match-adjusted to Ibr-treated arms of 1) ALPINE (NCT03734016) and 2) ELEVATE-RR (NCT02477696) for key baseline characteristics: age ≥75 y, bulky disease, ≥3 or ≥4 prior treatments, b2 microglobulin >3.5 mg/L, and del(11q) or del(17p). For comparison with ELEVATE-RR, only pts with del(17p) or del(11q) from RESONATE were included. After matching, adjusted ORR (CR + CRi + nPR + PR) and PFS from RESONATE were compared with published outcomes from ALPINE and ELEVATE-RR; for PFS, IPD for ALPINE and ELEVATE-RR were extracted from published Kaplan-Meier curves. Hazard ratios (HRs) were calculated using a weighted Cox model. Results: The analysis comprised 785 Ibr-treated pts across RESONATE (n = 195), ALPINE (n = 325), and ELEVATE-RR (n = 265). After omission of pts with missing values and the adjustment procedure, the effective RESONATE sample size was 95 pts (vs ALPINE) and 69 pts (vs ELEVATE-RR). Median follow-up was 36.0 versus 29.6 mo (RESONATE adjusted vs. ALPINE published) and 36.1 versus 40.9 mo (RESONATE adjusted vs. ELEVATE-RR published). 2-y PFS (95% CI) for Ibr-treated pts in RESONATE adjusted sample and ALPINE was 81% (74–90) and 66% (60–71), respectively; median PFS was 40.7 and 34.2 mo, with an HR (95% CI) of 0.57 (0.39–0.84) favoring RESONATE, P = 0.0048 (Figure). ORR (95% CI) was 90% (86–94) and 74% (69–79), respectively (P < 0.0001). Compared with the ELEVATE-RR Ibr arm, which included more pts with high-risk genetic features than ALPINE, the RESONATE adjusted sample had greater 2-y PFS (79% [69–89] vs. 69% [64–75], not statistically significant). Median PFS was 41.2 vs. 44.1 mo (HR [95% CI] 0.85 [0.55–1.31], P = 0.46), respectively; ORR was 89% (83–95) and 80% (75–85) (P = 0.0381). Encore Abstract - previously submitted to EHA 2023 The research was funded by: The research was funded by Pharmacyclics LLC, an AbbVie Company. Keywords: Chronic Lymphocytic Leukemia (CLL), Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. P. Ghia Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, Merck Sharp & Dohme, Bristol Myers Squibb, Janssen, Eli Lilly/Loxo Oncology, and Roche Honoraria: AbbVie, AstraZeneca, BeiGene, Merck Sharp & Dohme, Bristol Myers Squibb, Janssen, Eli Lilly/Loxo Oncology, and Roche Research funding: AbbVie, AstraZeneca, and Janssen T. Munir Consultant or advisory role: Morphosys and Sunesis Honoraria: AbbVie, AstraZeneca, Gilead, Janssen, and Novartis Other remuneration: travel/accommodation expenses from AbbVie, Gilead, or Janssen J. Burger Consultant or advisory role: BeiGene, Gilead, Janssen, Pharmacyclics, LLC, an AbbVie company, and TG Therapeutics Honoraria: Gilead, Janssen, Novartis, Pharmacyclics, LLC, an AbbVie company, and TG Therapeutics Other remuneration: travel/accommodation expenses from Gilead, Janssen, Pharmacyclics, LLC, an AbbVie company, and TG Therapeutics J. F. Seymour Research funding: AbbVie, Celgene, Janssen, and F. Hoffmann-La Roche Ltd. Other remuneration: speakers’ bureau with AbbVie, Celgene, and F. Hoffmann-La Roche Ltd.; patents, royalties, or other intellectual property with AbbVie; and expert testimony for F. Hoffmann-La Roche Ltd. K. Rogers Consultant or advisory role: Acerta Pharma, AstraZeneca, Beigene, Genentech, Innate Pharma, and Pharmacyclics, LLC, an AbbVie company Research funding: AbbVie, Genentech, Janssen, and Novartis Other remuneration: travel/accommodation expenses from AstraZeneca H. Huang Employment or leadership position: Everest Clinical Research and AbbVie Consultant or advisory role: Everest Clinical Research and AbbVie Research funding: Everest Clinical Research and AbbVie C. Moreno Consultant or advisory role: AbbVie, Ascentage, AstraZeneca, and Janssen Research funding: AbbVie and Janssen Other remuneration: speakers’ bureau for Janssen L. Neumayr Employment or leadership position: AbbVie Consultant or advisory role: ApoPharma Stock ownership: AbbVie Honoraria: Novartis Research funding: Pfizer and Sancilio Other remuneration: travel accommodations from Forma Therapeutics C. Abbazio Employment or leadership position: AbbVie Stock ownership: AbbVie and Bristol Myers Squibb J. Sharman Consultant or advisory role: AbbVie, AstraZeneca, and BeiGene Honoraria: AbbVie, ADC Therapeutics, AstraZeneca, BeiGene, Genentech, Lilly, Pharmacyclics, LLC, an AbbVie company, and TG Therapeutics

Matching adjusted indirect comparison of acupuncture versus fremanezumab in the preventive treatment of episodic migraine

Objective Acupuncture and fremanezumab are second-line treatments for migraine prophylaxis. We aimed to compare acupuncture with fremanezumab in the preventive treatment of episodic migraine by using a matching-adjusted indirect comparison analysis (MAIC). Methods We acquired participant-level data from an acupuncture trial recruiting 302 participants and summary-level data from a fremanezumab trial recruiting 875 participants (290 participants received monthly fremanezumab [MF] and 291 received single-dose fremanezumab [SF]). The primary outcome was the mean reduction in monthly headache days. The secondary outcomes were the mean reduction in monthly moderate-to-severe headache days, days with acute medication, and the adverse events rate. Results Before matching, the acupuncture arm had significantly lower BMI, fewer headache days with at least moderate severity, and fewer days with acute medication. After matching, the baseline variables were comparable between groups. The three arms had no difference in the change of monthly migraine days (MF vs. acupuncture: mean difference 0.3, 95%CI −0.5 to 1.1, p-value = 0.473; SF vs. acupuncture: mean difference 0.5, 95%CI −0.3 to 1.3, p-value = 0.214). The results were similar in the analyses of secondary outcomes sensitivity analyses. Thirty-six (25%) participants in the acupuncture arm reported adverse events, versus 192(66%) participants in the MF arm and 193 (66%) in the SF arm. Conclusion The preventive treatment effect of acupuncture is equivalent to fremanezumab, and it presented with a lower adverse event rate, which indicates that acupuncture can be an alternative to fremanezumab.

Clinical Efficacy of Sarilumab Versus Upadacitinib Over 12weeks: An Indirect Treatment Comparison.

The 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. Patient-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 12weeks. The 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. In the MAIC and STC analyses from TARGET and SELECT-BEYOND trials, the efficacy of sarilumab and upadacitinib were comparable.

On the double-robustness and semiparametric efficiency of matching-adjusted indirect comparisons.

Matching-adjusted indirect comparison (MAIC) enables indirect comparisons of interventions across separate studies when individual patient-level data (IPD) are available for only one study. Due to its similarity with propensity score weighting, it has been speculated that MAIC can be combined with outcome regression models in the spirit of augmented inverse probability weighting estimators to improve robustness and efficiency. We show that MAIC enjoys intrinsic double-robustness and semiparametric efficiency properties for estimating the average treatment effect on the treated in the limited IPD setting without explicit augmentation. A connection between MAIC and the method of simulated treatment comparisons is highlighted. These results clarify conditions under which MAIC is consistent and efficient, informing appropriate application and interpretation of MAIC analyses.

Improvement in Individual Symptoms and Total Symptom Score (TSS) and Matching-Adjusted Indirect Comparison (MAIC) Analysis to Compare TSS As a Continuous Endpoint in Patients with Myelofibrosis Treated with Pelabresib in Combination with Ruxolitinib Versus Janus Kinase Inhibitor Monotherapy

Background: Pelabresib (CPI-0610; PELA) is a bromodomain and extraterminal domain (BET) inhibitor in development for the treatment of myelofibrosis (MF). PELA combined with ruxolitinib (RUX) has shown a 56% response rate for ≥50% reduction in total symptom score (TSS) at Wk 24 from baseline (BL; TSS50) in Janus kinase inhibitor (JAKi) treatment-naïve patients (pts) with intermediate or high-risk MF in Arm 3 of the open-label Phase 2 MANIFEST study (NCT02158858). TSS50 is a standard measure of symptom improvement; however, the 50% response threshold does not capture clinical benefit in pts with TSS reduction <50% or pts who achieve TSS50 but could benefit from further symptom improvement (Dueck A, et al. European Hematology Association 2017. Poster E1331). Here, we present percentage change in TSS and subdomains as a continuous endpoint from Arm 3 of MANIFEST and indirect comparisons with historical double-blind JAKi trials in MF. Aims: To assess clinically meaningful changes in TSS with PELA in combination with RUX. TSS subdomains were analyzed to assess the underlying impact of PELA + RUX on symptom scores. In the absence of head-to-head studies of PELA + RUX vs JAKi monotherapy, naïve and matching-adjusted indirect comparison (MAIC) analysis (correcting for potential imbalances in baseline characteristics) were used to investigate improvement in TSS as a continuous endpoint in pts treated with PELA + RUX in Arm 3 of the MANIFEST study with historical double-blind Phase 3 JAKi trials: COMFORT-I (RUX), SIMPLIFY-1 (RUX, momelotinib [MOM]) and JAKARTA (fedratinib [FED]). Methods: In MANIFEST, percentage change in TSS and subdomains (fatigue, night sweats, itching, abdominal discomfort, pain under ribs, feeling of fullness and bone pain) from BL at Week (Wk) 12, 24, 36 and 48 were calculated. Pts with BL score = 0 were excluded. For the MAIC analysis, individual pt level data were available for MANIFEST Arm 3, and study-level data were extracted from published waterfall plots using WebPlotDigitizer (Rohatgia A. https://automeris.io/) for COMFORT-I, SIMPLIFY-1 and JAKARTA (FED 400 mg arm). Unanchored MAIC was conducted, whereby pts were reweighted to adjust for imbalances in key prognostic BL characteristics: gender, MF subtype, International Prognostic Scoring System risk status (IPSS), previous hydroxyurea use, platelet count, hemoglobin levels, spleen volume and JAK2V617F status; as a result, bias due to potential unmeasured differences is unlikely. The weights were used to calculate the effective sample size. Pts with IPSS intermediate-1 were excluded from the analysis. Weighted and unweighted treatment effects in terms of difference in least square (LS) means with their 95% confidence intervals using robust sandwich estimators for variance are presented. Studies used different TSS questionnaire versions; however, variations are subtle, and so comparisons across versions are valid (Dueck A, et al.Blood 2017;130:2168). Results: Comparable mean BL TSS scores were observed: 16.1 in MANIFEST Arm 3 and 17.5-19.4 across comparator Phase 3 studies. In MANIFEST Arm 3, a median reduction from BL of >50% was observed for TSS and all subdomains, and this reduction remained consistent across Wk 12 to Wk 48. TSS distribution in MANIFEST at Wk 24 showed greater median and mean reductions from BL vs JAKi monotherapy studies (Figure 1 shows comparison with RUX in SIMPLIFY-1). Complete summary level balance was achieved in the weighted distributions of the prognostic factors in MANIFEST Arm 3 versus comparators. After adjusting for imbalances, >20% greater reduction in LS mean percentage change in TSS from BL at Wk 24 was observed for all comparisons of MANIFEST Arm 3 vs historical studies, as shown in Figure 2. P values for all MAIC analyses were statistically significant. Conclusions: Analyzing TSS as a continuous endpoint in addition to responder analysis overcomes limitations of using TSS50 alone. TSS50 rates in MANIFEST Arm 3 were higher than all comparator MF studies, and clinically relevant improvements in TSS and its subdomains were observed as early as Wk 12 and were durable over time. When indirectly comparing Arm 3 of the Phase 2 MANIFEST study with historical Phase 3 MF studies using MAIC analysis, improved estimates of changes in TSS with PELA + RUX vs RUX, MOM or FED monotherapy were observed. A randomized Phase 3 MANIFEST-2 study of PELA + RUX vs RUX monotherapy in JAKi-naïve pts is ongoing (NCT04603495). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Matching Adjusted Indirect Comparisons of Personalized Prophylaxis with Simoctocog Alfa Versus Efmoroctocog Alfa, Damoctocog Alfa Pegol and Rurioctocog Alfa Pegol in Patients with Hemophilia a

Introduction: Prophylactic factor VIII (FVIII) therapy is the gold standard to prevent bleeding in patients with severe hemophilia A and should be individualized to patient needs. Although several FVIII products are available, the lack of head-to-head studies makes it difficult to compare their efficacy. The objective of this analysis was to indirectly compare the efficacy of personalized prophylaxis with simoctocog alfa (Nuwiq®) with three comparator FVIII products - efmoroctocog alfa (Eloctate®), damoctocog alfa pegol (Jivi®) and rurioctocog alfa pegol (Adynovate®) - among adults with severe hemophilia A. Methods: Matching adjusted indirect comparison (MAIC) methodology was used to estimate relative treatment effects during personalized prophylaxis after matching study populations with respect to clinically important baseline characteristics. Individual patient data (IPD) from 65 patients on personalized prophylaxis with simoctocog alfa in the NuPreviq study were compared with aggregated data for efmoroctocog alfa from 117 patients in the personalized prophylaxis arm of the A-LONG study, 110 patients treated with damoctocog alfa pegol in the PROTECT VIII study, and patients treated with rurioctocog alfa pegol in the FVIII target trough level 1-3% arm (57 patients) or the 8-12% arm (58 patients) from the PROPEL study. Following feasibility assessments for all proposed analyses, outcomes and matching variables were determined. Patients in the NuPreviq study who would have not met the inclusion criteria for the comparator studies were excluded from the analyses. Baseline age and body weight were used to re-weight the simoctocog alfa IPD such that the weighted summary statistics for simoctocog alfa matched those reported for efmoroctocog alfa; baseline age and body mass index were used for the comparison with damoctocog alfa pegol; and baseline age for the comparison with rurioctocog alfa pegol. Unanchored indirect treatment comparisons were then performed for each outcome using the weighted data for simoctocog alfa. Results: One patient from the NuPreviq study was excluded from the comparison with damoctocog alfa pegol based on baseline age, and 10 patients from the comparison with rurioctocog alfa pegol based on body weight. After matching the populations based on baseline characteristics, the effective sample sizes (ESS) for simoctocog alfa were 44, 40, 27, and 40 for the MAIC analyses with efmoroctocog alfa, damoctocog alfa pegol, and rurioctocog alfa pegol 1-3% and 8-12%, respectively (Table 1). The percentage of patients with zero bleeds was significantly higher with simoctocog alfa for three of the analyses (Figure 1, Table 1): simoctocog alfa (75%) vs efmoroctocog alfa (45%); simoctocog alfa (76.8%) vs damoctocog alfa pegol (38.2%); and simoctocog alfa (78.4%) vs rurioctocog alfa pegol 1-3% (42.1%). The percentage of patients with zero spontaneous bleeds was significantly higher for simoctocog alfa vs rurioctocog alfa pegol 1-3%; these data were not available for efmoroctocog alfa or damoctocog alfa pegol. The total annualized bleeding rates (ABRs) were generally lower with simoctocog alfa vs the comparators, but the difference only reached statistical significance vs damoctocog alfa pegol (Table 1). Spontaneous and joint ABRs were lower with simoctocog alfa vs rurioctocog alfa pegol 1-3%, but the differences were not statistically significant; these data were not available for efmoroctocog alfa or damoctocog alfa pegol. The mean weekly dose was significantly higher in patients treated with simoctocog alfa compared with comparator products: simoctocog alfa vs efmoroctocog alfa (101 vs 85 IU/kg), vs damoctocog alfa pegol (97 vs 70 IU/kg) and vs rurioctocog alfa pegol 1-3% (99 vs 74 IU/kg) (Table 1). Patients treated with simoctocog alfa required a significantly lower average weekly dose than those treated with rurioctocog alfa pegol 8-12% (99 vs 143 IU/kg). Dosing of all products was consistent with the respective prescribing information. Conclusions: The results of these indirect treatment comparisons indicate that pharmacokinetics-adjusted, individualized treatment with simoctocog alfa can lead to decreased ABRs and significantly increased zero bleed rates compared with extended half-life concentrates, albeit at a higher weekly dose. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Matching-adjusted indirect comparison of phase 3 clinical trial outcomes: OC-01 (varenicline solution) nasal spray and cyclosporine a 0.05% ophthalmic emulsion for the treatment of dry eye disease.

BACKGROUND: Matching-adjusted indirect comparison (MAIC) is a validated and widely accepted statistical method that derives indirect comparisons between treatments when head-to-head studies have not been performed. OBJECTIVE: To compare the efficacy of OC-01 varenicline nasal spray (OC-01 VNS) 0.03 mg to cyclosporine A (CsA) 0.05% ophthalmic emulsion on tear production in patients with dry eye disease based on data from the respective phase 3 clinical trials using the MAIC technique. METHODS: Individual patient data were drawn from the phase 3 registry trial of OC-01 VNS; aggregate data were drawn from 2 phase 3 trials of CsA in the publicly available New Drug Application for CsA 0.05% ophthalmic emulsion (RESTASIS). Using unanchored MAIC methods, the individual patient data were weighted based on 4 clinically relevant baseline variables (age, race, sex, and baseline Schirmer test score [STS]) to produce a weighted OC-01 VNS dataset matched to the key demographics of the CsA dataset. Least-squares mean change from baseline in STS for OC-01 VNS was calculated using the identical analysis of variance model used to calculate the same value for CsA in the RESTASIS New Drug Application, which were then compared. Proportions of subjects with improvement of 10 mm or more from baseline in STS were compared in the weighted OC-01 VNS and CsA dataset. Time points available for comparisons were CsA trials at 3 and 6 months and OC-01 data at 2 and 4 weeks. RESULTS: Data from 511 subjects in the OC-01 VNS phase 3 trial and 585 in the CsA phase 3 trials were analyzed. The least-squares mean STS change from baseline for OC-01 VNS at 2 and 4 weeks was significantly higher than that for CsA at 3 and 6 months (P < 0.0001 for all comparisons). Mean STS improvements were approximately 6-7 mm for OC-01 VNS and approximately 1 mm for CsA. The proportion of subjects with improvement of 10 mm or more from baseline in STS was significantly higher for OC-01 VNS (50.2%) than CsA (11.7 and 17.1% in the 2 CsA studies; P < 0.0001 for both comparisons). CONCLUSIONS: This MAIC analysis demonstrates OC-01 VNS produces significantly greater improvement in mean STS and results in significantly greater numbers of patients with substantial improvement in STS (percentage ≥ 10 mm) compared with CsA. Together, absent more robust data from head-to-head trials, findings may suggest a potentially greater magnitude of improvement achieved with OC-01 VNS compared with CsA for the treatment of dry eye disease within conditions of the analysis methodology. DISCLOSURES: Dr Visco was a consultant for Novartis, Allergan, and Oyster Point, Inc. Ms Hendrix and Drs Macsai and Gibson are employees and shareholders for Oyster Point Pharma, Inc. Drs Sun and Tam participated in clinical research and received funding from Oyster Point Pharma, Inc. Oyster Point Pharma, Inc sponsored the Phase 3 OC-01 (varenicine solution) clinical study from which analysis data are obtained.

Matching-adjusted indirect comparison of efficacy outcomes in trials of calcipotriol plus betamethasone dipropionate foam and cream formulations for the treatment of plaque psoriasis

Background and objectives Once-daily, fixed-combination calcipotriol 50 μg/g (Cal) plus betamethasone dipropionate 0.5 mg/g (BD) is available in aerosol foam and cream formulations. As no head-to-head data are available, we use a matching-adjusted indirect comparison (MAIC) approach to compare Cal/BD foam and cream. Methods Anchored and unanchored MAIC analyses were conducted using individual patient data (IPD) from five Cal/BD foam trials and two trials of Cal/BD cream. Outcomes of interest were the proportion of patients with Physician's Global Assessment (PGA) success and the mean reduction in modified Psoriasis Area and Severity Index (mPASI). Results In the anchored MAIC, patients were more likely to achieve PGA success after 4 weeks of Cal/BD foam than after 8 weeks of Cal/BD cream and had larger mean improvements in mPASI (p < .01 in EU mPASI analysis). In unanchored analyses, 4 weeks of Cal/BD foam treatment was statistically significantly more efficacious in inducing PGA success than 8 weeks of Cal/BD cream (p < .01 in five of six comparisons). Mean reductions in mPASI were consistently statistically significantly greater with Cal/BD foam than with Cal/BD cream. Conclusions Use of Cal/BD foam consistently shows significantly greater improvements in PGA and mPASI outcomes, compared with Cal/BD cream.