Panjabi, Sumeet

Objectives To investigate demographic, clinical characteristics, treatment patterns and healthcare resource utilisation (HCRU) among patients with portopulmonary hypertension (PoPH). Design Retrospective analysis of a real-world cross-sectional survey, the pulmonary arterial hypertension (PAH) Disease Specific Programme. Setting Secondary care settings in the USA. Participants Pulmonologists (n=22), cardiologists (n=17) and internists (n=7) who saw ≥2 patients with PAH/month provided data on 90 PoPH patients. Mean age of patients was 56.8 years, 51.1% were male, 76.7% were white/Caucasian. Primary and secondary outcome measures Demographic characteristics, initial presentation/diagnosis, disease trajectory, symptoms, comorbidities, treatment patterns and HCRU. Results The most common diagnostic tests were echocardiogram (62.2%), right heart catheterisation (56.7%) and electrocardiogram (48.9%). Dyspnea on exertion (64.4%), dyspnea following exertion (51.1%) and fatigue (48.9%) were the most common symptoms prior to PAH diagnosis as well as the most bothersome. Overall, 13.3% patients had mild disease before treatment vs 42.2% at time of survey. Most (60.0%) had stable disease (21.1% were improving and 18.8% were deteriorating at the time of the survey). Most common recent symptoms were dyspnea on exertion (51.1%), fatigue (37.8%) and dyspnea following exertion (32.2%). Patients had a mean of 1.8 comorbidities. In total, 80.0% of PoPH patients were receiving PAH-specific treatment; 41.7%, 22.2% and 12.5% received monotherapy, dual therapy and triple therapy, respectively. Patients had seen their physician 4.1 times in the past 12 months (3.5 visits specifically for PAH), while 31.1% had been hospitalised for PAH. Most (70.0%) patients were managed in a multidisciplinary team, and 8.9% of patients relied on a caregiver. Conclusions This study highlights the high symptomatic burden coupled with mostly moderate-to-severe disease status and a high hospitalisation rate despite the majority of PoPH patients being on therapy. Therefore, new treatment options in PoPH are in great need.

ImportanceA subgroup analysis of a randomized clinical trial established the efficacy of selexipag plus background therapy (monotherapy or double oral therapy [DOT]) vs placebo plus background therapy and found that the addition of selexipag within 6 months had an added benefit. However, the timing of selexipag addition to DOT and the incremental benefit in clinical practice is not well studied.ObjectiveTo compare triple oral therapy (TOT) consisting of selexipag, endothelin receptor antagonist (ERA), and phosphodiesterase type 5 inhibitor (PDE5i) vs DOT consisting of ERA and PDE5i.Design, Setting, and ParticipantsThis comparative effectiveness study was conducted using data from the US Komodo claims database to emulate a randomized trial. Patients aged 18 years or older with pulmonary arterial hypertension (PAH) treated with ERA plus PDE5i with records from July 2015 through June 2022 were duplicated to TOT and DOT and artificially censored when observed treatment deviated from assigned treatment. Hypothetical randomization was emulated using inverse probability of treatment weighting, and the study accounted for censoring-induced selection bias using inverse probability of censoring weighting. A pooled logistic model estimated the per-protocol difference between treatment groups. Data were analyzed from November 2022 through July 2023.InterventionsTOT (addition of selexipag within 3, 6, and 12 months of initiating DOT) vs DOT.Main Outcomes and MeasuresAdjusted risk of all-cause hospitalization, PAH-related hospitalization, and PAH-related disease progression over a 2-year follow-up.ResultsA total of 2966 patients with PAH (mean [SD] age, 54.3 [14.0] years; 2125 female [71.6%]) met eligibility criteria. Adding selexipag within 6 months of ongoing DOT was associated with a reduction in risk for all-cause hospitalization (adjusted hazard ratio [aHR], 0.82; 95% CI, 0.72-0.94), PAH-related hospitalization (aHR, 0.81; 95% CI, 0.70-0.95), and PAH-related progression (aHR, 0.82; 95% CI, 0.70-0.95) vs DOT alone. There were no associations if selexipag was initiated within 12 months for all-cause hospitalization, PAH-related hospitalization, or PAH-related disease progression. The association remained with a greater decrease in risk for disease progression vs DOT for selexipag initiation within 3 months (aHR, 0.74; 95% CI, 0.61-0.90).Conclusions and RelevanceThis study found that early selexipag addition to ERA plus PDE5i was associated with a reduction in risk of hospitalization and disease progression. These findings suggest that delays in selexipag initiation likely contribute to suboptimal patient and health system outcomes.

AbstractSelexipag is an oral selective agonist of the prostacyclin receptor approved to treat adults with pulmonary arterial hypertension (PAH). Selexipag is initiated at a dose of 200 μg twice daily (bid) and usually titrated up by 200 μg bid weekly (per label) or more slowly (e.g., every other week in real‐world clinical practice) to the highest tolerated individualized dose (ID) ranging from 200 to 1600 µg bid. In the Phase 3 GRIPHON trial, selexipag delayed disease progression and reduced risk of PAH‐related hospitalization compared with placebo; the effect was consistent across three prespecified ID groups: low (200–400 µg bid), medium (600–1000 µg bid), and high (1200–1600 µg bid). This study evaluated patient outcomes across selexipag dose ranges in real‐world practice. Data were analyzed from 1186 US adult patients with PAH on selexipag from the Komodo closed‐claims database (2015‒2022). Of these, 634 (53.5%) patients completed titration and reached their selexipag ID (43.8% high ID, 29.8% medium ID, 26.3% low ID). Subsequently, 72.4% of patients in the low ID group had dose adjustments compared with 61.9% (medium ID) and 34.5% (high ID; standardized mean difference 0.63). There were no significant differences in patient outcomes, i,e, persistence (time to discontinuation) and risk of all‐cause and PAH‐related hospitalization across ID groups. The findings in this diverse, real‐world population of patients with PAH reinforced an individualized approach to the dosing scheme to maximize benefit‐risk and achieve the highest tolerated dose with selexipag similar to findings from the GRIPHON trial and other studies.

Introduction: Pulmonary arterial hypertension (PAH) is a progressive, fatal disease associated with non-specific symptoms, which may lead to diagnosis delays and poor outcomes. Research Question: Which symptoms and diagnostic procedures occur prior to PAH diagnosis and do they vary based on diagnosis delay? Aim: To describe PAH symptoms and diagnostic procedures among patients newly diagnosed with PAH. Methods: Adults with PAH were identified from Optum’s de-identified Clinformatics ® Data Mart Database (2016-2021). Eligible patients had continuous health plan enrollment ≥12 months (mo) before the first recorded PAH-related symptoms (i.e., index date ) and from the index date until the first recorded PAH diagnosis on a medical claim (i.e., study period ). Patients also had ≥1 fill for a PAH treatment and ≥1 right heart catheterization at any time post-index. PAH symptoms and diagnostic procedures were described during the study period, overall, and stratified by time between the index date and first PAH diagnosis (i.e., diagnosis delay ; ≤12 mo, 12–24 mo, and >24 mo). Results: The sample included 538 patients (≤12 mo: N=327; 12–24 mo: N=126; >24 mo: N=85). Mean age was 66 years, 60.6% were female, and mean (range) diagnosis delay was 11.8 (0.0–50.2) mo. During the study period, most patients had ≥2 unique symptoms recorded, but those with longer delay had more fatigue (≤12 mo: 26.6%; 12–24 mo: 55.6%; >24 mo: 54.1%), edema (29.1%; 42.9%; 51.8%), and dizziness (10.1%; 23.0%; 18.8%), among others. Mean delay was shorter when the first symptoms were ascites (4.2 mo) and syncope (6.4 mo) and longer for fatigue (14.2 mo) and dizziness (14.0 mo). On average, patients with longer delay had more diagnostic procedures pre-diagnosis (≤12 mo: 4.3; 12–24 mo: 8.2; >24 mo: 8.7), driven by more electrocardiograms (ECG; 1.9; 4.2; 4.5). Overall, 85.5% of patients had an ECG and 83.5% had a transthoracic echocardiography pre-diagnosis. Conclusions: Symptoms such as fatigue, edema, and dizziness were more common in patients with longer time to diagnosis and these patients had more diagnostic procedures. Greater physician awareness and new screening tools (e.g., predictive algorithms using ECG data) could accelerate PAH diagnosis and treatment aiming at improving patient outcomes.

AbstractPulmonary arterial hypertension (PAH) is a rare, life‐limiting disease. PAH registries provide real‐world data that complement clinical trial data and inform treatment decisions. The TRIO comprehensive, integrated patient data repository (TRIO CIPDR), is an innovative US repository capturing data on contemporary patients diagnosed with pulmonary hypertension and receiving US Food and Drug Administration‐approved PAH therapies. This repository uniquely combines clinical data from electronic medical records with the ability to track drug‐prescription and drug‐dispensing characteristics, and includes 946 adult patients with PAH (data collected January 2019 to December 2020) enrolled from nine representative US specialist tertiary care centers. Potentially eligible patients were identified based on dispensing data from specialty pharmacies. Hemodynamic and clinical data, as well as dispensing information on prescribed PAH medications, were provided by tertiary centers. At enrollment, 75% of patients were female, 67% were White, median age at PAH diagnosis was 53 years (median time from diagnosis to enrollment was 5 years), and 37% were obese. Comorbidity profiles were as expected for a PAH population, although the proportion with atrial fibrillation (34%) was higher than expected. Overall, 38% of patients had idiopathic PAH and 30% had connective tissue disease‐related PAH. Among 917 patients receiving PAH‐specific therapy, 40% were on monotherapy, 43% on dual therapy, and 17% on triple therapy. Longitudinal data from this repository will allow tracking of the PAH treatment journey in relation to clinical characteristics and outcomes.

Introduction Carfilzomib dosing as a single agent or in combination with dexamethasone (Kd) has evolved from the initial 27 mg/m 2 twice-weekly (legacy dose), to more recently approved doses of 56 mg/m 2 twice-weekly and 70 mg/m 2 once-weekly (optimized doses). The objective of this study was to evaluate the overall survival (OS), and time to next treatment (TTNT) among multiple myeloma patients treated with Kd optimized vs legacy doses. Methods A retrospective analysis of patients receiving Kd between 01/01/2013–07/31/2017 was conducted using IQVIA’s oncology electronic medical records database. Kd dose was estimated based on body surface area. OS was measured from the Kd-initiation date until death. TTNT was defined as the time from Kd-initiation until the start of subsequent treatment. Kaplan-Meier analysis and Cox models were used to evaluate OS and TTNT. Results Of the 1,469 patients evaluated, 129 (8.8%) received optimized dose and 1,340 (91.2%) received legacy dose. Risk of mortality was 64% lower for patients receiving the optimized doses (HR: 0.36, 95% CI: 0.178–0.745). Patients receiving the optimized doses had significantly longer TTNT compared to patients receiving the legacy dose (median TTNT: 17.5 months [95% CI: 14.8-NE] and 13.2 months, [95% CI: 12.4–14.4], respectively; p = 0.023), and 33% lower risk of progressing to the subsequent treatment (HR: 0.67, 95% CI: 0.48–0.93). Conclusions Patient outcomes could be improved if eligible MM patients are treated with the optimized, recently approved Kd doses (56 mg/m 2 twice-weekly and 70 mg/m 2 once-weekly).

Abstract Background : Carfilzomib is an innovative second generation proteasome inhibitor (PI) that binds irreversibly and selectively to the proteasome. Carfilzomib exhibits sustained inhibition of the proteasome with minimal off-target activity. Kd was approved in 2016 as a treatment (Tx) option for R/RMM patients who have received one to three prior lines of therapy.In the ENDEAVOR phase 3, open label, multicenter randomized controlled trial assessing Kd vs Vd, median progression-free survival (PFS) was 18.7 months (95% CI:15.6 - could not be estimated) in the Kd group vs 9.4 months (8.4 - 10.4) in the Vd group at an a priori, pre-specified interim analysis (hazard ratio [HR]: 0.53 [95% CI: 0.44 - 0.65]; p<0.0001). OS data at the 1st interim analysis were immature. In the current study, we assessed the cost-effectiveness (CE) of Kd vs Vd from a US payer perspective using data from ENDEAVOR and long-term overall survival (OS) data from the Surveillance, Epidemiology, and End Results Program (SEER). Methods: A partitioned-survival model with a progression-free (PF), a post-progression (PP) and a death state was built with a 30 year horizon. PFS was modelled using separately fitted log-logistic parametric curves. In order to estimate measures of efficacy for OS and to incorporate treatment effect into the model, time-dependent multiple semiparametric Cox regression analyses were implemented for OS outcomes, which controlled for baseline covariates. OS for Vd in the base case was modelled with a separately fitted Weibull parametric curve, which was fitted to the Vd data. The time-dependent multiple Cox model generated a HR for 0 to 12 months and a HR beyond 12 months for Kd vs Vd, which were applied to model the Kd OS curve. The OS curves beyond 36 months were extrapolated with SEER data. A Weibull distribution was used for the extrapolation by matching the SEER registry data to the ENDEAVOR population, which was assumed to represent the Vd survival rate. To this extrapolated survival curve beyond 36 months, the OS treatment effect was applied in order to model the Kd curve. Grade ≥ 3 adverse events (AEs) with ≥ 2% incidence in any ENDEAVOR arm were included. Utilities were derived from the literature and adjusted for the treatment specific improvement in QoL observed when patients were PF in ENDEAVOR. Costs related to drug (WAC prices), administration, monitoring, AE management, and subsequent Tx were considered. The base case utilized OS results from an updated OS dataset (March 2016) that resulted in an ad hoc OS analysis. A 3% discount rate was applied to costs and health outcomes. Results: In the base-case, results from the model showed thatKd was more effective compared to Vd, providing 1.874 PfLY, 1.854 LY, and 1.654 QALY gains over the modelled horizon. Kd incurred $227,703 in total additional costs and the ICER vs Vd was 137,660$/QALY. Conclusions: The model predicts that Kd delivers 1.85 additional life years over the the comparator Vd. Per the base case, Kd is cost-effective vs Vd at generally accepted willingness-to-pay thresholds of $150,000/QALY and $300,000/QALY in the US. Based on the ENDEAVOR data, Kd is a superior PI-based doublet compared to Vd, and should be preferred whenever doublets are appropriate for the patient, Furthermore, this CE analysis shows that Kd delivers considerable incremental value to patients with relapsed or refractory MM and to payers who must allocate budgets for the treatment of patients. Table Table. Disclosures Jakubowiak: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Majer:Amgen Inc: Employment, Equity Ownership. Houisse:Amgen Inc: Consultancy. Benedict:Amgen Inc: Consultancy. Campioni:Amgen: Employment, Other: Holds Amgen Stock. Panjabi:Amgen Inc: Employment, Equity Ownership. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy.

Introduction Data on the economic burden of disease progression among multiple myeloma (MM) patients who have had a stem cell transplant (SCT) in the US are limited. This study evaluated the impact of disease progression on healthcare resource utilization (HRU) and costs among these patients in the US. Methods Adult patients (pts) with a confirmed MM diagnosis (Dx), defined as ≥1 inpatient or ≥2 non-diagnostic outpatient claims 30-365 days apart who initiated a course of MM therapy (Rx) during the study period (Jan 1, 2006 to Dec 31, 2016) and received SCT during the first year after the initial diagnosis of MM were identified from the Truven Analytics MedStat MarketScan® Commercial Claims and Encounters and Medicare and Coordination of Benefits databases. The first date with Dx for MM was defined as the "Dx date" and line of therapy (LOT) was identified based on an adaptation of a previously-developed algorithm. Pts were excluded if they had a gap in enrollment during the period beginning 6-month before the Dx date through 30-days after the first LOT (1L) initiation date, received MM Rx, unclassified antineoplastic medications, or SCT before the Dx date, or had missing information required to identify LOT or assess baseline characteristics or study outcomes. The 12 months after initiation of each LOT was designated the "event identification period" for progression. Disease progression was defined as advancement to next LOT, diagnosis or procedure codes indicative of bone metastasis, hypercalcemia, soft tissue plasmacytoma, skeletal related events, or acute kidney disease while off MM Rx, or death. The "event date" for progression was defined as date with evidence of progression. For each pt with progression, one pt without progression was randomly selected and assigned an event date to ensure that the distribution of time from LOT initiation to event date for pts without progression was the same as the distribution of time from LOT initiation to event date for pts with progression. For each LOT (L1-L3), annual HCRU and costs from index date, defined as 30-day before the event date, through disenrollment or end of the study period were compared for pts with vs without progression using inverse probability of treatment weighting (IPTW) to adjust for differences between groups in baseline characteristics including year of index date, age, gender, region, plan type, Medicare status, comorbidities, and pre-index HRU and healthcare costs. All costs were adjusted to 2016 US $. In a subgroup analysis, HCRU and costs were evaluated for LOTs initiated from 2013 to 2016 to reflect patterns of treatment in current era. Results Of the 28,184 adult MM pts who received ≥1 MM Rx during the study period, 3226 qualified for the study, including 837 pts with progression and 2389 without progression during 1L. The corresponding numbers for 2L, and 3L were 412 and 589, and 226 and 196, respectively. Mean age at index date was 57 years; 57% were male. After IPTW, all baseline characteristics were well balanced in all LOTs with standardized mean differences <0.1 for most baseline characteristics. The mean number of hospitalizations per year was greater for pts with progression in all LOTs, with differences ranging from 1.11 (95%CI 0.85, 1.37) for 2L to 0.34 (95%CI 0.21, 0.47) for 1L. In all LOTs, annual costs of inpatient and outpatient services were greater for pts with progression while costs of outpatient prescriptions were greater among patient without progression. Total healthcare costs were greater for pts with vs without progression in all LOTs with hospitalizations and outpatient visit costs being key drivers. Total incremental annual costs in those who progressed were higher by $13,386 (1L), $105,004 (2L), and $70,206 (3L). When the analysis was restricted to LOTs initiated between 2013 and 2016, the incremental costs in pts who progressed were generally greater in the most recent era: $43,381 (1L), $113,797 (2L), and $115,327 (3L). Conclusions For MM pts receiving drug Rx and SCT the economic burden of disease progression is substantial across all LOTs. Incremental costs of progression are largely attributable to hospitalizations and outpatient visits. Treatments that prevent or delay progression are likely to yield important reductions in downstream disease management costs. These savings should be considered in frameworks assessing the value of innovative treatments for MM. Disclosures Fonseca: AbbVie, Amgen, Bayer, Celgene, Kite, Janssen, Juno, Merck, Pharmacylics, Sanofi, Takeda: Other: Consultant/Advisor; Prognosticatin of MM based on Genetic Categorization by FISH: Patents & Royalties; Adaptive Biotechnologies: Other: Scientific Advisory Board. Hagiwara:Amgen Inc.: Research Funding. Panjabi:Amgen Inc.: Employment, Other: Owns Amgen stock, Research Funding. Yucel:Amgen Inc.: Employment, Other: Owns Amgen stock, Research Funding. Buchanan:Amgen Inc.: Employment, Other: Owns Amgen stock, Research Funding. Delea:Amgen Inc.: Research Funding.

Aim To compare healthcare resource use and costs between newly diagnosed multiple myeloma (NDMM) patients with and without skeletal-related events (SREs). Methods Adults newly diagnosed with MM (1 January 2006 and 30 June 2017) with at least 12 months continuous health coverage prior to diagnosis were identified using the IBM MarketScan administrative claims. To control for baseline differences, NDMM patients with SREs were propensity score matched to NDMM patients without SREs. Outcomes included annual HRU and costs during follow-up along with number and type of SREs (SRE cohort only). Patients with SREs were stratified by number of SREs, and annual SRE-related costs were reported. Student's t test and Chi-squared test were used to compare outcomes. Results Before matching, the 6648 patients in the SRE cohort had more comorbidities, were more likely to have MM treatment, and had higher pre-index healthcare costs than the 7458 patients in the non-SRE cohort. After matching, cohorts of 3432 patients were well balanced on baseline characteristics. Patients with SREs (vs. without SREs) had significantly higher inpatient, outpatient, and pharmacy HRU. Patients with SREs had significantly higher mean annual all-cause healthcare costs ($213,361 vs. $94,896, p < 0.001) with hospitalization being the leading driver of increased costs (38.7% of total). Among 6648 patients with SREs, the mean annual SRE-related healthcare costs were $39,603, $45,463, and $50,111 for patients with one, two, and three or more events, respectively. Conclusions NDMM patients with SREs have more than twice the all-cause healthcare costs than matched patients without SREs. Costs increase with the number of SRE events.