A Retrospective, Longitudinal Registry Study on the Long-Term Durability of Ivacaftor Treatment in People with Cystic Fibrosis.

INTRODUCTION: Ivacaftor (IVA) has been shown to change the trajectory of cystic fibrosis (CF) disease progression by slowing the rate of lung function decline in clinical studies. Long-term real-world data help to confirm the durability of this response. METHODS: This non-interventional, longitudinal study used data from the US CF Foundation Patient Registry to describe the annualized rate of change in lung function in people with CF receiving IVA. The IVA-treated cohort included people with CF aged ≥ 6 years who had ≥ 1 CF transmembrane conductance regulator (CFTR)-gating mutation and initiated IVA between 31 January 2012 and 31 December 2018. An age-matched comparator cohort included people with CF heterozygous for the F508del-CFTR mutation and a minimal function mutation (R117H excluded) and had not received CFTR modulator therapy. Baseline characteristics were balanced using standardized mortality ratio (SMR) weights computed from estimated propensity scores. The annualized rate of change in percent predicted forced expiratory volume in 1 s (ppFEV1) was estimated over 5 years and used to calculate the relative annualized rate of change in lung function in the IVA-treated versus comparator cohorts. RESULTS: In the 5-year follow-up period, 548 people were in the IVA-treated and 541 in the comparator cohorts after SMR weighting. The annualized rate of change in ppFEV1 over 5 years was -1.23 (95% CI -1.45, -1.03) and -2.03 (-2.16, -1.90) percentage points in the IVA-treated and comparator cohorts, respectively. There was a 39% reduction (95% CI: 28, 50) in the rate of lung function decline in the IVA-treated versus comparator cohort over 5 years. Findings were generally consistent with those of shorter follow-up periods. CONCLUSION: IVA showed a durable clinical benefit by slowing the rate of lung function decline over 5 years. Results support a sustained and consistent impact of IVA on lung function trajectory in people with CF. Word count: 300 (limit: 300 words).

Improved Health Outcomes in Patients with Systemic Lupus Erythematosus Following Early Belimumab Initiation Without Prior Immunosuppressant Use: A Real-World Descriptive Study.

INTRODUCTION: Patients with systemic lupus erythematosus (SLE) have variable treatment pathways, including antimalarials, glucocorticoids, immunosuppressants, and/or biologics. This study describes differences in clinical outcomes when initiating belimumab (BEL) before and after immunosuppressant use. METHODS: This real-world, retrospective cohort study (GSK Study 217536) used de-identified administrative claims data from January 2015 to December 2022 in the Komodo Health Database. Adults with moderate/severe SLE initiating BEL (index date) were identified from January 2017 to May 2022, allowing a ≥ 24-month baseline period. Patients were stratified into those initiating BEL before immunosuppressant use (no immunosuppressant use within 24 months before index) and those initiating BEL after immunosuppressant use (one immunosuppressant used within 24 months before index). Oral glucocorticoid (OGC) use, SLE flares, new organ damage, and all-cause healthcare resource utilization (HCRU) were analyzed descriptively over a 24-month follow-up. RESULTS: Baseline SLE severity was similar for patients initiating BEL before (n = 2295) versus after (n = 4114) immunosuppressant use (moderate, 83.1% vs 79.0%; severe, 16.8% vs 21.0%). Patients initiating BEL before versus after immunosuppressant use had lower SLE flare rates and OGC use. Post-index, patients initiating BEL before versus after immunosuppressant use discontinued their OGC sooner (moderate baseline SLE, 4.5 vs 8.9 months; severe baseline SLE, 6.2 vs 11.6 months). Patients initiating BEL before versus after immunosuppressant use had lower SLE flare rates per person-year at all time points (especially severe flare rates in patients with severe baseline SLE, 0.70 vs 1.48 through 24 months post-index). Median time to new organ damage occurrence was longer in patients initiating BEL before versus after immunosuppressant use (moderate baseline SLE, 32.1 vs 26.7 months; severe baseline SLE, 22.7 vs 21.6 months). All-cause HCRU was similar between cohorts. CONCLUSIONS: These results suggest that patients initiating BEL before versus after immunosuppressant use had more favorable outcomes.

Long-term impact of ivacaftor on mortality rate and health outcomes in people with cystic fibrosis.

BACKGROUND: Ivacaftor (IVA) has been shown to improve lung function and other clinical outcomes in people with cystic fibrosis (CF). A decade of real-world IVA availability has enabled the examination of long-term outcomes with this treatment. This retrospective, longitudinal cohort study investigated the impact of IVA on mortality rate and health outcomes among people with CF in the US. METHODS: Data from the US CF Foundation Patient Registry from January 2010 to December 2019 were analysed. The IVA-treated cohort included people with a CF transmembrane conductance regulator (CFTR) gating mutation (excluding R117H); age-matched comparator cohort included people with a F508del and a minimal function CFTR mutation who had no prior CFTR modulator treatment. Baseline characteristics were balanced between cohorts using standardised mortality ratio weighting generated from propensity scores. Outcomes of interest were overall survival, lung transplant, percent predicted forced expiratory volume in 1 s (ppFEV1), body mass index (BMI), pulmonary exacerbations (PEx), outpatient visits and hospitalisations. FINDINGS: Over a maximum follow-up of 7.9 years, the IVA-treated cohort (N=736) had lower rates of mortality (hazard ratio [HR] (95% CI): 0.22 (0.09 to 0.45)), lung transplant (HR: 0.11 (95% CI 0.02 to 0.28)), PEx (rate ratio: 0.49 (95% CI 0.42 to 0.55)) and all-cause hospitalisations (rate ratio: 0.50 (95% CI 0.43 to 0.56)) as well as better lung function (mean difference in ppFEV1: 8.46 (95% CI 7.34 to 9.75)) and higher BMI/BMI z-scores (mean difference 1.20 (95% CI 0.92 to 1.71) kg/m2 and 0.27 (95% CI 0.25 to 0.40), respectively) than the comparator cohort (N=733). INTERPRETATION: Our analysis suggests that IVA provides sustained clinical benefits in people with CF over a follow-up period of approximately 8 years. These findings reinforce the existing real-world evidence that IVA can slow disease progression and decrease the healthcare burden of CF over the long term.

Impact of age at ivacaftor initiation on pulmonary outcomes among people with cystic fibrosis.

BACKGROUND: Ivacaftor (IVA) improves lung function and other extrapulmonary outcomes in people with cystic fibrosis (CF). However, the effect of initiating IVA at earlier versus later ages has not been studied. METHODS: We conducted an observational cohort study of people in the US CF Foundation Patient Registry aged ≥6 years with ≥1 CF transmembrane conductance regulator-gating mutation to compare the effects of initiating IVA at earlier ages on per cent predicted forced expiratory volume in 1 s (ppFEV1) and pulmonary exacerbation (PEx) outcomes. People with CF were grouped by age at IVA initiation (ages 6-10, 11-15, 16-20 and 21-25 years) to perform three analyses of younger versus older IVA initiation (6-10 vs 11-15, 11-15 vs 16-20 and 16-20 vs 21-25 years). For each analysis, baseline characteristics assessed over 1-year periods at the same age prior to IVA initiation were balanced by standardised mortality/morbidity ratio (SMR) weighting. For each analysis, outcomes were compared over a 5-year outcome assessment period when both groups were in the same age range and receiving IVA. FINDINGS: Baseline characteristics were well balanced between younger and older IVA initiator groups after SMR weighting. In the outcome assessment period, younger IVA initiators had significantly higher mean ppFEV1 than older initiators across all comparisons, and those initiating IVA between ages 6-10 and 11-15 years had significantly lower PEx rates. INTERPRETATION: Study findings showed the importance of early IVA initiation in people with CF.

Treatment Patterns and Clinical Outcomes Among Patients With Metastatic Prostate Cancer Harboring Homologous Recombination Repair Mutations.

BACKGROUND: There is currently limited literature assessing the real-world treatment patterns and clinical outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) mutations. METHODS: Medical charts were abstracted for mCRPC patients with ≥ 1 of 12 HRR somatic gene alterations treated at US oncology centers participating in the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange. Treatment patterns and clinical outcomes were assessed from the initiation of first-line or later (1L+) mCRPC therapy received on or after July 1, 2014. RESULTS: Among 138 patients included in the study, the most common somatic HRR mutations were CDK12 (47.8%), BRCA2 (22.5%), and ATM (21.0%). Novel hormonal therapy and taxane chemotherapy were most commonly used in 1L; taxane use increased in later lines. Median overall survival (95% confidence interval [CI]) was 36.3 (30.7-47.8) months from initiation of 1L therapy and decreased for subsequent lines. Similarly, there was a trend of decreasing progression-free survival and prostate-specific antigen response from 1L to 4L+ therapy. CONCLUSIONS: Treatment patterns identified in this study were similar to those among patients with mCRPC regardless of tumor HRR mutation status in the literature.

Comparative effectiveness of lenalidomide/dexamethasone-based triplet regimens for treatment of relapsed and/or refractory multiple myeloma in the United States: An analysis of real-world electronic health records data.

BACKGROUND: This retrospective longitudinal study compared the effectiveness of dexamethasone+lenalidomide (Rd)-based triplet regimens containing proteasome inhibitors (PIs) ixazomib (IRd), carfilzomib (KRd), and bortezomib (VRd) or monoclonal antibodies (MABs) elotuzumab (ERd) and daratumumab (DRd) in patients with relapsed/refractory multiple myeloma (RRMM)-including those with high cytogenetic risk-primarily treated at community oncology clinics in the United States. METHODS: Electronic health records of adult RRMM patients in a deidentified real-world database (01/01/2014-09/30/2020) who initiated IRd, KRd, VRd, ERd, or DRd in the second or later line of therapy (LOT) were analyzed. The index date was the date of initiation of each LOT and baseline was the 6-month pre-index period. Duration of therapy (DOT), time to next therapy (TTNT), progression-free survival (PFS), and overall survival (OS) were compared across regimens with multivariable Cox proportional hazards models. RESULTS: Of the 1,185 patients contributing 1,332 LOTs, 985 had standard cytogenetic risk (median age, 71 years) and 180 had high risk (median age, 69 years). Compared with other regimens, DRd was associated with longer DOT overall (adjusted hazard ratio [95 % confidence interval]: 1.84 [1.42, 2.38] vs. KRd, 1.65 [1.20, 2.28] vs. ERd, 1.58 [1.23, 2.04] vs. IRd, and 1.54 [1.18, 2.00] vs. VRd), and longer TTNT and PFS. KRd was associated with shorter OS compared with DRd (1.45 [1.01, 2.08]) and VRd (1.32 [1.01, 1.73]). High-risk patients had similar outcomes with all triplet regimens. CONCLUSION: Although DRd improved clinical outcomes overall, Rd-based triplet regimens containing a PI or MAB are similarly effective in high-risk RRMM.

Real-World Effectiveness of Sotrovimab for the Early Treatment of COVID-19: Evidence from the US National COVID Cohort Collaborative (N3C).

BACKGROUND AND OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has been an unprecedented healthcare crisis, one that threatened to overwhelm health systems and prompted an urgent need for early treatment options for patients with mild-to-moderate COVID-19 at high risk for progression to severe disease. Randomised clinical trials established the safety and efficacy of monoclonal antibodies (mAbs) early in the pandemic; in vitro data subsequently led to use of the mAbs being discontinued, without clear evidence on how these data were linked to outcomes. In this study, we describe and compare real-world outcomes for patients with mild-to-moderate COVID-19 at high risk for progression to severe COVID-19 treated with sotrovimab versus untreated patients. METHODS: Electronic health records from the National COVID Cohort Collaborative (N3C) were used to identify US patients (aged ≥ 12 years) diagnosed with COVID-19 (positive test or ICD-10: U07.1) in an ambulatory setting (27 September 2021-30 April 2022) who met Emergency Use Authorization (EUA) high-risk criteria. Patients receiving the mAb sotrovimab within 10 days of diagnosis were assigned to the sotrovimab cohort, with the day of infusion as the index date. Untreated patients (no evidence of early mAb treatment, prophylactic mAb or oral antiviral treatment) were assigned to the untreated cohort, with an imputed index date based on the time distribution between diagnosis and sotrovimab infusion in the sotrovimab cohort. The primary endpoint was hospitalisation or death (both all-cause) within 29 days of index, reported as descriptive rate and adjusted [via inverse probability of treatment weighting (IPTW)] odds ratio (OR) and 95% confidence interval (CI). RESULTS: Of nearly 2.9 million patients diagnosed with COVID-19 during the analysis period, 4992 met the criteria for the sotrovimab cohort, and 541,325 were included in the untreated cohort. Before weighting, significant differences were noted between the cohorts; for example, patients in the sotrovimab cohort were older (60 years versus 54 years), were more likely to be white (85% versus 75%) and met more EUA criteria (mean 3.1 versus 2.2) versus the untreated cohort. The proportions of patients with 29-day hospitalisation or death were 3.5% (176/4992) and 4.5% (24,163/541,325) in the sotrovimab and untreated cohorts, respectively (unadjusted OR: 0.78; 95% CI: 0.67, 0.91; p = 0.001). In adjusted analysis, sotrovimab was associated with a 25% reduction in the odds of hospitalisation or death compared with the untreated cohort (IPTW-adjusted OR: 0.75; 95% CI: 0.61, 0.92; p = 0.005). CONCLUSIONS: Sotrovimab demonstrated clinical effectiveness in preventing severe outcomes (hospitalisation, mortality) in the period 27 September 2021-30 April 2022, which included Delta and Omicron BA.1 variants and an early surge of Omicron BA.2 variant.

Real-World Treatment Patterns and Clinical Outcomes With Brentuximab Vedotin or Other Standard Therapies in Patients With Previously Treated Cutaneous T-Cell Lymphoma in the United States.

INTRODUCTION/BACKGROUND: Primary cutaneous anaplastic large-cell lymphomas (pcALCLs) are a type of cutaneous T-cell lymphoma (CTCL) in which CD30 is uniformly expressed. In mycosis fungoides (MF), another CTCL, CD30 is heterogeneously expressed. In ALCANZA, patients with pcALCLs or CD30-positive MF randomized to brentuximab vedotin (BV) vs. physician's choice of methotrexate or bexarotene had significantly improved outcomes, including higher objective response rates (ORR) lasting ≥4 months (ORR4), as well as longer median progression-free survival (PFS) and time to next treatment (TTNT). In this study, we sought to assess the real-world impact of treatment with BV in second or later lines of therapy for CTCL. MATERIALS AND METHODS: This retrospective chart review describes patient characteristics, treatment patterns, clinical outcomes, and healthcare resource use (HRU) in patients with pcALCLs or MF previously treated with ≥1 systemic therapy and subsequently treated with BV (n = 139) or other standard therapy (OST; n = 164). RESULTS: Most patients in the BV cohort (96.4%) received BV as second-line (2L) systemic therapy. The most common OSTs were methotrexate (11.6%), mogamulizumab (9.1%), and bendamustine (9.1%) monotherapies. For 2L BV and OST, median duration of therapy was 8.4 and 5.2 months, real-world ORR was 82.1% and 66.5%, and real-world ORR4 was 42.5% and 25.0%. Real-world 1- and 2-year PFS, TTNT, and OS were significantly longer (all P < .01) and HRU was lower for BV vs. OST. CONCLUSION: These real-world outcomes are consistent with ALCANZA results, demonstrating favorable outcomes with BV vs. OST in patients with CTCL previously treated with ≥1 systemic therapy.

Patient-centric assessment of rheumatoid arthritis using a smartwatch and bespoke mobile app in a clinical setting.

Rheumatoid arthritis (RA) is a fluctuating progressive disease requiring frequent symptom assessment for appropriate management. Continuous tracking using digital technologies may provide greater insights of a patient's experience. This prospective study assessed the feasibility, reliability, and clinical utility of using novel digital technologies to remotely monitor participants with RA. Participants with moderate to severe RA and non-RA controls were monitored continuously for 14 days using an iPhone with an integrated bespoke application and an Apple Watch. Participants completed patient-reported outcome measures and objective guided tests designed to assess disease-related impact on physical function. The study was completed by 28 participants with RA, 28 matched controls, and 2 unmatched controls. Completion rates for all assessments were > 97% and were reproducible over time. Several guided tests distinguished between RA and control cohorts (e.g., mean lie-to-stand time [seconds]: RA: 4.77, control: 3.25; P < 0.001). Participants with RA reporting greater stiffness, pain, and fatigue had worse guided test performances (e.g., wrist movement [P < 0.001] and sit-to-stand transition time [P = 0.009]) compared with those reporting lower stiffness, pain, and fatigue. This study demonstrates that digital technologies can be used in a well-controlled, remote clinical setting to assess the daily impact of RA.

Comparison of health care costs and resource utilization for commonly used proteasome inhibitor-immunomodulatory drug-based triplet regimens for the management of patients with relapsed/refractory multiple myeloma in the United States.

BACKGROUND: Economic differences among currently available proteasome inhibitors (PI)-based lenalidomide-dexamethasone (Rd)-backbone triplet regimens-ixazomib (I), bortezomib (V), and carfilzomib (K) plus Rd-remain poorly understood. OBJECTIVE: To assess health care resource utilization (HCRU) and health care costs of patients with relapsed/refractory multiple myeloma (RRMM) in the United States treated with IRd, VRd, and KRd. METHODS: This retrospective longitudinal cohort study using IQVIA PharMetrics Plus adjudicated claims US data (January 1, 2015, to September 30, 2020) included adult patients with all available data who initiated IRd, VRd, or KRd in second line of therapy or later (LOT2+) on or after September 1, 2015. The index date was the treatment initiation date for each LOT (multiple LOTs per patient were included) and the baseline was 6 months pre-index. MM-related and all-cause HCRU/costs were assessed during follow-up and reported per patient per month (PPPM; 2020 US Dollars). For MM-related costs only, treatment administration costs were excluded from outpatient (OP) costs and instead summed with pharmacy costs. HCRU/costs were compared between treatment groups using generalized linear models (GLMs). Cost variables were compared using 2-part models and GLM with log transformation and γ distribution. Inverse probability of treatment weighting (IPTW) adjusted for imbalance of baseline confounders across treatment groups. RESULTS: The study included 511 patients contributing 542 LOTs (IRd: n = 153; VRd: n = 262; KRd: n = 127). Before IPTW, mean observed time spent on therapy was 8.5, 9.3, and 7.3 months for the IRd, VRd, and KRd cohorts, respectively. During follow-up and after IPTW, IRd and VRd were associated with significantly fewer OP visits vs KRd. Post-IPTW comparisons of MM-related costs for IRd vs KRd yielded lower OP costs for IRd (mean diff. PPPM: -$3,428; P < 0.001), contributing to lower total medical costs (-$3,813; P < 0.001) and total health care cost savings with IRd vs KRd (-$5,813; P = 0.001). MM-related OP costs were lower for VRd (mean diff. PPPM: -$3,543; P < 0.001) than KRd, reducing its total MM-related medical costs (-$3,997; P = 0.002), leading to total MM-related health care cost savings with VRd vs KRd (-$12,357; P < 0.001). All-cause cost comparisons yielded similar results (total health care cost savings for IRd and VRd vs KRd: -$6,371 and -$13,629, respectively; all P < 0.001). CONCLUSIONS: From the US insurance-payer perspective, patients treated with IRd and VRd had significant medical cost savings vs KRd due to lower OP costs when excluding treatment administration costs. The differential economic impacts of PI-Rd regimens in this study may help to inform treatment decisions for patients with MM. DISCLOSURES: This study and article were supported by Takeda Development Center Americas, Inc. Dr Sanchez has no conflicts to declare. Dr Chari has the following relationships: Research Support/Principal Investigator: Amgen, Array Biopharma, Celgene, Glaxo Smith Klein, Janssen, Millenium/Takeda, Novartis Pharmaceuticals, Oncoceutics, Pharmacyclics, Seattle Genetics; Consultant: Amgen, Bristol-Myers Squibb, Celgene, Millenium/Takeda, Janssen, Karyopharm; Scientific Advisory Board: Amgen, Celgene, Millenium/Takeda, Janssen, Karyopharm, Sanofi, Seattle Genetics. Drs Cherepanov, Huang, Dabora, and Noga are current employees of Takeda, while Drs Stull and Young are ex-employees of Takeda; Drs Cherepanov and Huang also own stocks in Takeda. Dr DerSarkissian, Ms Cheng, Ms Zhang, Mr Banatwala, and Dr Duh are employees of Analysis Group, Inc. (AG), a consulting firm that received funding from Takeda to conduct this study. Ms Pi was an employee of AG at the time of the study. Dr Ailawadhi has the following relationships to declare: Research Support and Consulting for BMS, GSK, and Janssen; Research Support from AbbVie, Arch Oncology, Cellectar, Medimmune, Pharmacyclics, and Xencor; Consulting for Beigene, Oncopeptides, Regeneron, Sanofi, and Takeda.