Year Of Treatment In Patients Research Articles

Efficacy and safety profile of 2-year netakimab treatment in patients with moderate-to-severe plaque psoriasis in terms of the randomized double-blind placebo-controlled BCD-085-7/PLANETA clinical trial

Background. Netakimab, a recombinant humanized monoclonal antibody, specifically binding to IL-17 blocks its activity resulting in plaque psoriasis signs decrease. The results of the first year of BCD-085-7/PLANETA study showed high efficacy and a favorable safety profile in the treatment of patients with moderate-to-severe psoriasis.
 Aims. Efficacy and safety assessments of netakimab through 2 years of treatment in patients with moderate-to-severe psoriasis.
 Materials and methods. BCD-085-7/PLANETA study is ongoing Randomized, Double-blind, Placebo-Controlled Phase III clinical study. In the study, 213 patients with moderate-to-severe plaque psoriasis were randomly assigned to one of three study groups. In the first two groups of patients, after weekly drug administration, received netakimab at a dose of 120 mg every two or four weeks. In the third group the patients received placebo. During 12-week double-blind study period the efficacy were evaluated based on the proportion of patients achieved PASI 75. After that all patients were switched to netakimab (once in 4 weeks). Patients who failed to achieve PASI 75 at Week 52 were withdrawn from the study. The open period lasts about 3 years. Herein we focus on the results of 2-year netakimab treatment (120 mg, weekly for 3 weeks, then once in 4 weeks), the recommended per label dose. Taking into account the epidemiological situation (COVID-19) and results limitation due to missing visits, additionally to the efficacy analysis in patients received, at least, one dose of netakimab, analysis in those of them who had relevant data on each visit per Protocol was conducted (ITT and PP populations).
 Results. At Year 1, PASI 75/90/100 responses were achieved in 88,7/74,5/56,6% patients, respectively (ITT-population) and in 100/85/66% patients, respectively (ITT-population). In 2 year, 69,3/58,0/40,6% sustained their responses in ITT-population and 93,2/78,2/53,1% in PP-population. Through 2 years, the high quality of life sustained among patients. The safety profile remained favorable and immunogenicity was low.
 Conclusions. Treatment with netakimab at a dose of 120 mg every 4 weeks results in high rates of sustained clinical response and quality life improvement in patients with moderate-to-severe plaque psoriasis with remains of a favorable safety profile.

FC056: Early Reductions in Proteinuria with Voclosporin Treatment Across Lupus Nephritis Biopsy Classes: Pooled Data from the AURA-LV AND AURORA 1 Trials

Abstract BACKGROUND AND AIMS Voclosporin, a novel calcineurin inhibitor, was approved by the FDA for the treatment of adults with active lupus nephritis (LN) in combination with background immunotherapy, and was successfully tested in two pivotal trials, AURA-LV (Phase 2) and AURORA 1 (Phase 3). Pooled data from these trials showed that the addition of voclosporin to mycophenolate mofetil (MMF) and low-dose steroids resulted in significantly higher complete renal response (CRR) rates at 24 weeks and 1 year of treatment in patients with LN. More patients in the voclosporin group achieved urine protein creatinine ratio (UPCR) reductions of ≥ 50% from baseline, and the median time to this endpoint was significantly shorter in the voclosporin group compared with the control group. Reduced proteinuria at 1 year is the best predictor of improved long-term renal outcomes in LN.[1,2] The current report evaluates the impact of voclosporin on the time to proteinuria reduction by biopsy class in pooled data from the AURA-LV and AURORA 1 trials. METHOD Both trials enrolled patients with biopsy-proven LN (Class III, IV or V ± III/IV) within 6 months (or up to 2 years in AURORA 1) and proteinuria ≥ 1.5 mg/mg (≥2 mg/mg for Class V). The pooled analysis included 268 patients in the voclosporin (23.7 mg BID) group and 266 patients in the control group. All patients received MMF (target 1 g BID) and low-dose steroids (target dose 2.5 mg/day by week 16 according to protocol-defined steroid taper). For this post-hoc analysis, hazard ratios (HR) for the times to UPCR ≤ 0.5 mg/mg and UPCR reduction ≥ 50% from baseline were analyzed by biopsy class. RESULTS The addition of voclosporin resulted in faster times to both UPCR ≤ 0.5 mg/mg and UPCR reduction ≥ 50% from baseline in the overall study population and across individual biopsy classes (HR > 1; Table 1). Median times to UPCR of ≤ 0.5 mg/mg and UPCR reduction ≥ 50% from baseline for both pure Class III and pure Class IV were significantly shorter for patients treated with voclosporin than the respective control groups: 142 versus 372 days (Class III) and 142 versus ND (not determinable) days (Class IV) for UPCR ≤ 0.5 mg/mg; 25 versus 84 days (Class III) and 29 versus 57 days (Class IV) for UPCR reduction ≥ 50% from baseline. The differences between the voclosporin and control groups for pure Class III and pure Class IV were apparent within the first month of treatment and sustained at 1 year. Similar results were seen with mixed Class III/V and IV/V. Patients with pure Class V took the longest to achieve both UPCR endpoints; the difference between groups was not statistically significant. CONCLUSION Patients treated with voclosporin in addition to MMF and low-dose steroids achieved earlier reductions in proteinuria across all biopsy classes. As expected, patients with Class V disease took longer to reach both UPCR endpoints than patients with proliferative disease, suggesting this population of patients may require a longer duration of treatment. This analysis further supports the efficacy results observed in the individual AURA-LV and AURORA 1 trials, indicating faster time to response when voclosporin is added to standard of care agents MMF and steroids.

COVID-19 Outcomes and Vaccination in People with Relapsing Multiple Sclerosis Treated with Ofatumumab.

IntroductionThe SARS-CoV-2 pandemic necessitated better understanding of the impact of disease-modifying therapies on COVID-19 outcomes and vaccination. We report characteristics of COVID-19 cases and vaccination status in ofatumumab-treated relapsing multiple sclerosis (RMS) patients.MethodsCOVID-19 data analyzed were from the ongoing, open-label, long-term extension phase 3b ALITHIOS study from December 2019 (pandemic start) and post-marketing cases from August 2020 (ofatumumab first approval) up to 25 September 2021. COVID-19 cases, severity, seriousness, outcomes, vaccination status, and breakthrough infection were evaluated.ResultsAs of 25 September 2021, 245 of 1703 patients (14.4%) enrolled in ALITHIOS receiving ofatumumab (median exposure: 2.45 years) reported COVID-19 (confirmed: 210; suspected: 35). Most COVID-19 was of mild (44.1%) or moderate (46.5%) severity, but 9% had severe/life-threatening COVID-19. There were 24 serious cases (9.8%) with 23 patients hospitalized; 22 recovered and 2 died. At study cut-off, 241 patients (98.4%) had recovered or were recovering or had recovered with sequelae and 2 (0.8%) had not recovered. Ofatumumab was temporarily interrupted in 39 (15.9%) patients. Before COVID-19 onset, IgG levels were within the normal range in all COVID-19–affected patients, while IgM was < 0.4 g/l in 23 (9.4%) patients. No patient had a reinfection. Overall, 559 patients were vaccinated (full, 476; partial, 74; unspecified, 9). Breakthrough infection was reported in 1.5% (7/476) patients, and 11 reported COVID-19 after partial vaccination. As of 25 September 2021, the Novartis Safety Database (~ 4713 patient-treatment years) recorded 90 confirmed COVID-19 cases receiving ofatumumab. Most cases were non-serious (n = 80), and ten were serious (1 medically significant, 9 hospitalized, 0 deaths). Among 36 of 90 cases with outcomes reported, 30 recovered and 6 did not recover.ConclusionCOVID-19 in RMS patients on ofatumumab was primarily of mild/moderate severity and non-serious in these observational data. Most recovered from COVID-19 without treatment interruption. Two people died with COVID-19. Breakthrough COVID-19 despite being fully/partially vaccinated was uncommon.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-022-00341-z.

Exposure-adjusted safety analyses of the VISION phase 3 trial of 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer.

85 Background: In the VISION trial, targeted radioligand therapy with 177Lu-PSMA-617 significantly prolonged radiographic progression free survival (rPFS) and overall survival when added to standard of care (SoC) in patients with advanced prostate-specific membrane antigen (PSMA)-PET-positive metastatic castration-resistant prostate cancer. There was a higher incidence of treatment-emergent adverse events (TEAEs) with 177Lu-PSMA-617 + SoC vs SoC. However, treatment exposure was more than three times longer in the 177Lu-PSMA-617 + SoC arm and thus relative toxicity may have been overestimated. A post hoc analysis of the relationship between exposure and frequency of TEAEs was performed to facilitate comparison of rates between arms. Methods: In this international, open-label study, adult patients previously treated with ≥ 1 androgen receptor pathway inhibitors and 1–2 taxane regimens were randomized 2:1 to 177Lu-PSMA-617 (7.4 GBq Q6W, ≤ 6 cycles) + SoC or SoC. Safety was a secondary endpoint. TEAEs (regardless of causality) were reported from start of randomized treatment for up to 30 days after last treatment administration (including SoC) or 1 day before subsequent anticancer treatment, whichever occurred first. Overall TEAE incidence was adjusted for treatment exposure by calculating incidence per 100 patient treatment-years (PTY). The analysis was performed for the first occurrence of TEAEs. Results: Exposure-adjusted incidence of any grade, grade ≥ 3 and selected TEAEs are listed in the table. There was similar exposure-adjusted incidence of gastrointestinal events and fatigue and higher exposure-adjusted incidence of musculoskeletal and renal events with SoC compared with 177Lu-PSMA-617 + SoC suggesting an association with treatment exposure rather than 177Lu-PSMA-617. Dry mouth, dry eye and acute myelosuppression maintained a higher incidence, confirming relationship with 177Lu-PSMA-617 treatment. Conclusions: The adjusted safety analysis, accounting for a longer safety observation due to longer rPFS in patients receiving 177Lu-PSMA-617, reveals a comparable incidence of TEAEs between arms. This confirms a favorable risk/benefit profile of 177Lu-PSMA-617 added to SoC in this patient population. Clinical trial information: NCT03511664. [Table: see text]

Abstract P1-13-07: De-escalation of five-year adjuvant endocrine therapy in patients with ER-low positive breast cancer: Propensity-matched analysis from a prospectively maintained cohort

Abstract Background The standard 5 years of endocrine therapy has shown additional benefits when compared with short-term 2-3 years of treatment in patients with estrogen receptor (ER)-positive breast cancer; however, whether the long-term treatment is still necessary for ER-low positive (1%-10% by immunohistochemistry) breast cancer is unclear. Methods The prospectively maintained Breast Surgery Database of Fudan University Shanghai Cancer Center was used for this propensity-matched analysis. The primary endpoint was disease-free survival (DFS). Multivariate Cox regression and propensity score matching methods were performed to minimize bias. Hazard ratio (HR) with 95% confidence interval (CI) was calculated. All statistics were 2-sided. Results From 2012 to 2017, there were 22768 consecutive women with pathologically confirmed early-stage breast cancer and 1013 (4.45%) were identified as ER-low positive. Among them, 634 cases met the inclusion criteria and were divided into three groups: received no endocrine therapy (n=89); received 2-3 years of endocrine therapy (n=185); and received approximately 5 years of endocrine therapy (n=360). At a median follow-up of 65 months, there was no significant difference in DFS between patients who received 2-3 years and 5 years of endocrine therapy (HR, 0.82; 95% CI: 0.51-1.33; P=0.43). In the multivariate Cox regression analysis of the propensity score-matched samples, the DFS was not significantly better for patients who received 5 years of endocrine therapy than those receiving 2-3 years of treatment (HR, 0.74; 95% CI: 0.41-1.31; P=0.30). Conclusion Short-term 2-3 years of endocrine therapy might be an alternative for ER-low positive breast cancer instead of standard 5 years. Citation Format: Keda Yu, Yuwen Cai, Zhiming Shao. De-escalation of five-year adjuvant endocrine therapy in patients with ER-low positive breast cancer: Propensity-matched analysis from a prospectively maintained cohort [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-13-07.

Rates and predictors of methotrexate-related adverse events in patients with early rheumatoid arthritis: results from a nationwide UK study.

ObjectivesTo estimate prevalence rates and identify baseline predictors of adverse events (AEs) over the first year of treatment in patients with RA starting MTX.MethodsData came from the UK Rheumatoid Arthritis Medication Study (RAMS), a prospective cohort of patients with RA starting MTX. This analysis included patients aged ≥18 years with physician diagnosed RA and symptom duration ≤2 years, who were commencing MTX for the first time. AEs were recorded by interviewing patients at 6- and 12-month follow-up visits. The period prevalence rates of AEs are reported for 0–6 months, 6–12 months and 0–12 months of follow-up. The associations between baseline characteristics and AEs were assessed using multivariable logistic regression.ResultsA total of 1069 patients were included in the analysis. Overall, 77.5% experienced at least one AE. The most commonly reported AEs were: gastrointestinal (42.0%), neurological (28.6%), mucocutaneous (26.0%), pulmonary (20.9%), elevated alanine transaminase (18.0%) and haematological AEs (5.6%). Factors associated with increased odds of AEs were: women vs men (gastrointestinal, mucocutaneous, neurological) and alcohol consumption (nausea, alopecia, mucocutaneous). Older age, higher estimated glomerular filtration rate and alcohol consumption were associated with less reporting of haematological AEs.ConclusionsAEs were common among patients over the first year of MTX, although most were not serious. Knowledge of the rates and factors associated with AE occurrence are valuable when communicating risks prior to commencing MTX. This can help patients make informed decisions whether to start MTX, potentially increasing adherence to treatment.

New criteria of effectiveness of anti-VEGF therapy in exudative age-related macular degeneration

To evaluate the effectiveness of anti-angiogenic therapy using fluctuation and variability in patients with exudative age-related macular degeneration (AMD). This study included 200 patients with types 1, 2, 3 neovascularization and polypoidal choroidal vasculopathy (PCV). All patients underwent standard ophthalmological examination, as well optical coherence tomography (OCT) and OCT angiography (OCT-A). Patients were divided into 4 quartiles based on fluctuation and variability. All patients underwent intravitreal administration of the anti-VEGF drug aflibercept (Eylea) manufactured by Bayer, Germany, using the Treat-and-Extend regimen. As a result of the study, a significant increase in visual acuity was revealed on the second year of treatment in patients in the 2nd and 3rd quartiles, best corrected visual acuity (BCVA) decreased in the 1st and 4th quartiles. In the group with paracentral fluctuation, a significant increase in BCVA by the end of the second year of treatment was observed in the 1st (p=0.05) and 3rd quartiles. As a result of a 2-year follow-up, it was found that BCVA values were lower in patients with the greatest variability (2nd, 3rd, and 4th quartiles). A significant increase in BCVA was observed in the 1st quartile (p=0.047). The largest number of patients with subretinal fibrosis that had fluctuations in the central zone and peripheral fluctuations was observed in the 4th quartile, the smallest - in the 2nd quartile. Similar pattern was observed in the variability group. In the setting of anti-VEGF therapy, a significant increase in BCVA was observed in patients with the lowest variability - in the 1st quartile (p=0.047), but in patients with fluctuations the highest BCVA values were observed in the 2nd and 3rd quartiles, while in the 4th quartile BCVA decreased (p=0.0562). The results of this study indicate that when treating patients with neovascular AMD, clinicians should aim for a treatment strategy that minimizes fluctuation and variability.

Adjuvant Imatinib Treatment for 5 Years versus 3 Years in Patients with Ruptured Localized Gastrointestinal Stromal Tumor: A Retrospective Analysis.

PurposeThree years of adjuvant imatinib is the standard treatment for resected gastrointestinal stromal tumors (GISTs) with rupture, but the recurrence rate is prominently high. We aimed to investigate the efficacy and safety of 5-year adjuvant imatinib compared with 3-year treatment in patients with a ruptured GIST following surgical resection.Materials and MethodsA total of 51 patients were included in the analysis. The assessment of GIST rupture was based on Nishida’s classification. Twenty patients who were diagnosed before November 2013 were treated with 5 years of imatinib, and 31 patients who were diagnosed after November 2013 were treated with 3 years of imatinib. We retrospectively compared the clinical outcomes of the two groups.ResultsBaseline characteristics and the incidence of the adverse events were generally comparable between the two groups. During a median follow-up duration of 43.8 months and 104.2 months in the 3- and 5-year group, 8 and 9 patients had a disease recurrence, respectively. The 5-year group showed better recurrence-free survival (RFS) than the 3-year group. In multivariate analysis, low mitotic index was a significant independent favorable prognostic factor for RFS, while 5-year imatinib treatment was marginally associated with a favorable RFS.ConclusionFive years of adjuvant imatinib treatment in patients with ruptured GIST was associated with favorable survival outcomes with manageable toxicity profiles. Our findings warrant validation and confirmation in future studies.

Bimekizumab response maintenance through two years of treatment in patients with moderate to severe plaque psoriasis who responded after 16 weeks: Interim results from the BE BRIGHT open-label extension trial

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Safety, Immunogenicity and Interchangeability of Biosimilar Monoclonal Antibodies and Fusion Proteins: A Regulatory Perspective.

BackgroundBiosimilars have been used for 15 years in the European Union (EU), and have been shown to reduce costs and increase access to important biological medicines. In spite of their considerable exposure and excellent safety record, many prescribers still have doubts on the safety and interchangeability of biosimilars, especially monoclonal antibodies (mAbs) and fusion proteins.ObjectivesThe aim of this study was to analyse the short- and long-term safety and interchangeability data of biosimilar mAbs and fusion proteins to provide unbiased information to prescribers and policy makers.MethodsData on the safety, immunogenicity and interchangeability of EU-licensed mAbs and fusion proteins were examined using European Public Assessment Reports (EPARs) and postmarketing safety surveillance reports from the European Medicines Agency (EMA). As recent biosimilar approvals allow self-administration by patients by the subcutaneous route, the administration devices were also analyzed.ResultsPrelicensing data of EPARs (six different biosimilar adalimumabs, three infliximabs, three etanercepts, three rituximabs, two bevacizumabs, and six trastuzumabs) revealed that the frequency of fatal treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation of treatment, serious adverse events (SAEs), and main immune-mediated adverse events (AEs) were comparable between the biosimilars and their reference products. The availability of new biosimilar presentations and administration devices may add to patient choice and be an emerging factor in the decision to switch patients. Analysis of postmarketing surveillance data covering up to 7 years of follow-up did not reveal any biosimilar-specific adverse effects. No product was withdrawn for safety reasons. This is in spite of considerable exposure to biosimilars in treatment-naïve patients and in patients switched from the reference medicinal product to the biosimilar. Analysis of data from switching studies provided in regulatory submissions showed that single or multiple switches between the originator and its biosimilar versions had no negative impact on efficacy, safety or immunogenicity.ConclusionsIn line with previous reports of prelicensing studies of biosimilar mAbs and etanercepts, this study demonstrated comparable efficacy, safety, and immunogenicity compared with the reference products. This is the first study to comprehensively analyze postmarketing surveillance data of the biosimilar mAbs and etanercept. An analysis of more than 1 million patient-treatment years of safety data raised no safety concerns. Based on these data, we argue that biosimilars approved in the EU are highly similar to and interchangeable with their reference products. Thus, additional systematic switch studies are not required to support the switching of patients.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40265-021-01601-2.

Effect of far infrared therapy on arteriovenous fistula maturation, survival and stenosis in hemodialysis patients, a randomized, controlled clinical trial: the FAITH on fistula trial

BackgroundAn arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis treatment. After creation many of the AVFs will never mature or if functioning will need an intervention within 1 year due to an AVF stenosis. Studies investigating possible therapies that improves the AVF maturation and survival are scarce. Far infrared therapy (FIR) has shown promising results. In minor single centre and industry supported trials FIR has shown improved AVF maturation and survival. There is a need of a randomized multicentre controlled trial to examine the effect of FIR on the AVF maturation and survival and to explore the possible AVF protective mechanism induced by the FIR treatment.MethodsThis investigator initiated, randomized, controlled, open-labeled, multicenter clinical trial will examine the effect of FIR on AVF maturation in patients with a newly created AVF (incident) and AVF patency rate after 1 year of treatment in patients with an existing AVF (prevalent) compared to a control group. The intervention group will receive FIR to the skin above their AVF three times a week for 1 year. The control group will be observed without any treatment. The primary outcome for incident AVFs is the time from surgically creation of the AVF to successful cannulation. The primary outcome for the prevalent AVFs is the difference in number of AVFs without intervention and still functioning in the treatment and control group after 12 months. Furthermore, the acute changes in inflammatory and vasodilating factors during FIR will be explored. Arterial stiffness as a marker of long term AVF patency will also be examined.DiscussionFIR is a promising new treatment modality that may potentially lead to improved AVF maturation and survival. This randomized controlled open-labelled trial will investigate the effect of FIR and its possible mechanisms.Trial registrationClinicaltrialsgov NCT04011072 (7th of July 2019).

26581 Maintenance of complete skin clearance throughout 3 years of continuous guselkumab treatment in patients with moderate-to-severe psoriasis: A post hoc analysis of 5-year data from the VOYAGE 1 trial

Introduction and objectives: This post hoc analysis of VOYAGE 1 study 5-year data aimed to evaluate the baseline characteristics of patients achieving complete skin clearance (Psoriasis Area and Severity Index [PASI] of 0) for ≥156 consecutive weeks of guselkumab treatment.

Economic Evaluation for the US of Ibrutinib Versus Allogeneic Hematopoietic Stem-Cell Transplantation for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia with 17p Deletion

Background: Prior to targeted therapies, allogeneic hematopoietic stem cell transplantation (HSCT) was the primary therapy for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) with 17p deletion (del(17p)). Treatment options now include oral ibrutinib, which produces significant progression free (PFS) and overall survival (OS) with acceptable safety and the convenience of being non-invasive. Complete remission is unlikely and ibrutinib is not considered curative. HSCT has curative potential, but is associated with high upfront cost, potential transplant-related morbidity and mortality (incl. graft-versus-host disease) and potential relapse. Both treatments are expensive with relative differences in cost of treatment and supportive care management. Considering these different profiles, we performed cost-effectiveness and cost-utility analyses of ibrutinib versus HSCT in R/R CLL del(17p) from a US payer perspective.Methods: Three-year and life time horizon Markov models were constructed specifying 3 health states: PFS with embedded sub-states specifying whether patient (pt) is on or off therapy, progression, and death. Data sources to simulate the R/R CLL del(17p) pts included O'Brien et al (Lancet Oncol 2016) for ibrutinib and Schetelig et al (J Clin Oncol 2008) for HSCT. Kaplan-Meier PFS and OS curves were digitized, PFS and OS data extracted, and Weibull distributions fitted for both ibrutinib and HSCT. Cost of ibrutinib was sourced from RedBook. Costs of HSCT procedure, pre-conditioning treatment, and post-procedural side effects were estimated from published prediction equations and national claims database. EQ-5D utilities were sourced from published literature; side effect disutilities were assumed same for both interventions. A discount rate of 3% was applied when survival exceeded one year. Following extrapolation to the 3-year and life time horizons, the life years (LY) and quality adjusted LY (QALY) for each treatment were estimated, and the incremental LY and QALY gained with ibrutinib over HSCT calculated. Total treatment costs, cost differentials, and the incremental cost effectiveness (ICER) and cost utility ratios (ICUR) were determined. Base case analyses were validated by probabilistic sensitivity analyses (PSA).Results: Ibrutinib prevailed in PFS and OS over HSCT over the 3-year horizon, when curves crossed and HSCT prevailed in PFS and OS over the life time horizon, hence the separate analyses. In the 3-year Markov model, compared to HSCT, ibrutinib showed cost savings of $48,642 (PSA: $48,678), incremental gains of 0.23 (PSA: 0.22) LY and 0.20 (PSA: 0.19) QALY, yielding an ICER of savings of -$211,487 (PSA: -$221,246) per LY gained and an ICUR of savings of -$243,210 (PSA: -$256,200) per QALY gained (Table). In contrast, in the life time Markov model, ibrutinib showed an incremental cost of $25,802 (PSA: $23,317), incremental gains of 0.12 (PSA: 0.09) LY and 0.13 (PSA: 0.11) QALY, yielding an ICER of $215,016 (PSA: $259,077) per LY gained and an ICUR of $198,476 (PSA: $211,972) per QALY gained.Conclusion: Against a 3-year time horizon, ibrutinib prevails in OS and PFS over HSCT in the management of patients with R/R CLL del(17p). As it is also cost saving, it has the 3-year benefit of being clinically superior in combined efficacy and safety at lower cost; but without curative potential. Against a life time horizon, ibrutinib still prevails in OS and PFS over HSCT but less so, is no longer cost saving as treatment costs continue, and attains cost effectiveness at a willingness-to-pay threshold of ~$260,000. This is due to survival curves crossing at ~160 weeks for PFS and ~140 weeks for OS, indicating lower PFS and OS probabilities for HSTC-treated patients over the first ~3 years. In contrast to their lower survival probabilities over that time period, surviving HSCT-treated patients had a higher likelihood of subsequent PFS and OS than ibrutinib-treated patients, indicating a potential curative effect in some patients. While the long-term curative potential of HSCT merits clinical consideration for young and fit patients, the lower survival probability in the first three years of treatment should be noted and may be relevant for elderly and less fit patients. Ibrutinib provides significantly greater clinicoeconomic value over the first three years of treatment in patients with R/R CLL del(17p) versus HSCT while the benefit declines beyond 3 years. [Display omitted] DisclosuresPersky:Genentech: Consultancy; MorphoSys: Other: Independent Data Monitoring Committee member ; Verastem: Consultancy; Spectrum Pharmaceuticals: Research Funding. Abraham:Janssen Oncology (Johnson & Johnson, LLC): Consultancy.

The risk of malignancy in patients with secukinumab‐treated psoriasis, psoriatic arthritis and ankylosing spondylitis: analysis of clinical trial and postmarketing surveillance data with up to five years of follow‐up

Data on the use of biologic therapy and malignancy risk are inconsistent due to limited long-term robust studies. To assess the malignancy risk in patients with secukinumab-treated psoriasis, psoriatic arthritis (PsA) and ankylosing spondylitis (AS). This integrated safety analysis from both the secukinumab clinical trial programme and postmarketing safety surveillance data included any patient receiving at least one approved dose of secukinumab with a maximum of 5 years of follow-up. Safety analyses evaluated the rate of malignancy using exposure-adjusted incidence rates [EAIR; incidence rates per 100 patient treatment-years (PTY)]. Standardized incidence ratios (SIRs) were reported using the Surveillance, Epidemiology, and End Results Program (SEER) database as a reference population. Crude incidence of malignancy was also reported using postmarketing surveillance data. Safety data from 49 clinical trials with secukinumab-treated patients were included: 10 685 patients with psoriasis, 2523 with PsA and 1311 with AS. Across indications over a 5-year period, the EAIR of malignancy was 0·85 per 100 PTY [95% confidence interval (CI) 0·74-0·98] in secukinumab-treated patients, corresponding to 204 patients per 23 908 PTY. Overall, the observed vs. expected number of malignancies from secukinumab clinical trial data were comparable, as indicated by an SIR of 0·99 (95% CI 0·82-1·19) across indications. The estimated crude cumulative incidence reporting rate per 100 PTY for malignancy was 0·27 in the postmarketing surveillance data across indications with a cumulative exposure of 285 811 PTY. In this large safety analysis, the risk of malignancy was low for up to 5 years of secukinumab treatment. These data support the long-term use of secukinumab in these indications.

Risk of requiring a walking aid after 6.5years of ocrelizumab treatment in patients with relapsing multiple sclerosis: Data from the OPERA I and OPERA II trials.

Background and purposeRequiring a walking aid is a fundamental milestone in multiple sclerosis (MS), represented by an Expanded Disability Status Scale (EDSS) score ≥6.0. In the present study, we assess the effect of ocrelizumab (OCR) on time to EDSS score ≥6.0 in relapsing MS.MethodsTime to EDSS score ≥6.0 confirmed for ≥24 and ≥48 weeks was assessed over the course of 6.5 years (336 weeks) in the double‐blind period (DBP) and open‐label extension (OLE) period of the OPERA I (NCT01247324) and OPERA II (NCT01412333) studies.ResultsTime to reach EDSS score ≥6.0 was significantly delayed in those initially randomized to OCR versus interferon. Over 6.5 years, the risk of requiring a walking aid confirmed for ≥24 weeks was 34% lower among those who initiated OCR earlier versus delayed treatment (average hazard ratio [HR] DBP + OLE 0.66, 95% confidence interval [CI] 0.45–0.95; p = 0.024); the risk of requiring a walking aid confirmed for ≥48 weeks was 46% lower (average HR DBP+OLE 0.54, 95% CI 0.35–0.83; p = 0.004).ConclusionThe reduced risk of requiring a walking aid in earlier initiators of OCR demonstrates the long‐term implications of earlier highly effective treatment.

P191 Secukinumab demonstrates a consistent safety profile in patients with psoriasis, psoriatic arthritis and ankylosing spondylitis over long term: updated pooled safety analyses

P191 Secukinumab demonstrates a consistent safety profile in patients with psoriasis, psoriatic arthritis and ankylosing spondylitis over long term: updated pooled safety analyses

P134 Radiographic progression of structural joint damage over 5 years of baricitinib treatment in patients with RA: results from RA-BEYOND

Abstract Background/Aims Baricitinib (BARI) is an oral, reversible, selective JAK1/2 inhibitor. Treatment with once-daily oral BARI resulted in low rates of radiographic progression for up to 2 years in patients with rheumatoid arthritis (RA). Here, we evaluate the radiographic progression of structural joint damage in patients with RA over 5 years of treatment with BARI. Methods This included patients who completed three Phase 3 trials, RA-BEGIN (DMARD-naive), RA-BUILD (csDMARD-IR), or RA-BEAM (MTX-IR), and enrolled in long-term extension study, RA-BEYOND. Patients receiving blinded BARI at the conclusion of Phase 3 trials remained on that dose (2mg/4mg, once daily) in RA-BEYOND. At 52 weeks, DMARD-naive patients receiving methotrexate(MTX) or combination therapy(BARI 4mg+MTX) were switched to BARI 4mg monotherapy; MTX-IR patients receiving adalimumab(ADA) were switched to BARI 4mg on background MTX. At 24 weeks, csDMARD-IR patients receiving placebo(PBO) were switched to BARI 4mg on background csDMARD. Analysis population included patients who had baseline and at least one radiograph collected after 2 years. Radiographic progression of structural joint damage (Years 3-5) was determined by changes from baseline in van der Heijdemodified Total Sharp Score(ΔmTSS), erosion score, and joint space narrowing. Proportion of patients showing no progression was assessed based on change from baseline mTSS(ΔmTSS) from originating study, using thresholds of 0.5 or smallest detectable change(SDC). Mixedmodel repeatedmeasures and logistic regression models were used to analyze continuous variables and categorical variables, respectively; linear extrapolation was used for imputation of missing data(maximum of 1 year). Results 82.6% (2125/2573) of patients entered long-term extension study. Among DMARD-naive patients, those on initial BARI monotherapy or in combination with MTX had significantly slower radiographic progression(ΔmTSS) versus those on initial MTX at Years 3, 4, 5 (p ≤ 0.05). They had significantly fewer erosions at these time points (p ≤ 0.05). A greater proportion of patients who received initial BARI therapy and BARI+MTX had no radiographic progression versus initial MTX monotherapy using thresholds of 0.5 (p ≤ 0.05). Among MTX-IR patients, those on initial BARI treatment had slower radiographic progression compared to PBO and results were comparable to those on initial ADA treatment at Years 3, 4, 5. A greater proportion of patients who received initial BARI therapy had no radiographic progression versus initial PBO using thresholds of SDC (p ≤ 0.05). Among csDMARD-IR patients, although differences between groups were small, patients on initial BARI 4mg had slowest radiographic progression compared to initial PBO and initial BARI 2mg. At least 74% of the structure data used in the analyses are based on observed data. Conclusion Treatment with once-daily oral BARI maintained low rates of radiographic progression for up to 5 years in different patient populations with RA. Disclosure D.M.F.M. van der Heijde: Consultancies; AbbVie, Amgen, Astellas, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Cyxone, Daiichi Sankyo, Eli Lilly and Company, Galapagos NV, Gilead Sciences, Janssen, Merck Sharp &amp; Dohme, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, and UCB Pharma. C.E. Kartman: Shareholder/stock ownership; Eli Lilly and Company. L. Xie: Shareholder/stock ownership; Eli Lilly and Company. S. Beattie: Shareholder/stock ownership; Eli Lilly and Company. D.E. Schlichting: Shareholder/stock ownership; Eli Lilly and Company. P. Durez: Member of speakers’ bureau; Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, and Sanofi. Y. Tanaka: Member of speakers’ bureau; AbbVie, Asahi-kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly and Company, GlaxoSmithKline, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer, Sanofi, Takeda, UCB, and YL Biologics. Grants/research support; AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, MSD, Ono, and Taisho-Toyama and Takeda. R. Fleischmann: Consultancies; AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Novartis, Pfizer, Roche, Sanofi-Aventis, and UCB.

Effect of Ixekizumab on Patient Reported Outcomes and Quality of Life in Patients With Moderate-to-Severe Plaque Psoriasis: 5-Year Results from the UNCOVER-1 and -2 Studies.

We describe patient-reported outcomes and quality of life through 5 years of treatment in patients with moderate-to-severe plaque psoriasis in the UNCOVER-1 and -2 studies. This analysis included patients who were randomized to ixekizumab every 2 weeks then received ixekizumab every 4 weeks during the maintenance period, and who achieved static physician global assessment (0,1) at week 12, completed week 60, and entered the long-term extension period (weeks 60&ndash;264). Outcomes measures included responses in itch numeric rating scale (NRS), skin pain visual analog scale (VAS), and dermatology life quality index (DLQI) (0,1), and mean change from baseline in short form health survey (SF-36) mental (MCS) and physical component summaries (PCS), psoriasis skin appearance bothersomeness (PSAB), and work productivity activity impairment (WPAI). At week 264 in UNCOVER-1 and -2, the observed itch NRS &ge;4 responses were 82.4% and 93.1%, respectively, the itch NRS=0 responses were 51.7% and 58.5%, respectively, the skin pain VAS=0 responses were 59.3% and 63.1%, respectively, and the DLQI (0,1) responses were 75.0% and 88.1%, respectively. The observed mean changes from baseline at week 264 in UNCOVER-1 and UNCOVER-2 were 3.4 and 6.5, respectively, for SF-36 MCS, 4.4 and 4.8, respectively, for SF-36 PCS, and -21.3 and -22.0, respectively, for PSAB. WPAI psoriasis item scores improved from baseline in both UNCOVER-1 and -2. Ixekizumab provided clinically meaningful and sustained improvements in itch, skin pain, DLQI, PSAB, SF-36 PCS, SF-36 MCS, and WPAI through 5 years of treatment in patients with moderate-to-severe plaque psoriasis. J Drugs Dermatol. 20(4):394-401. doi:10.36849/JDD.5821Visit the JDD Psoriasis Resource Center for more.

Investigation of ALPL variant states and clinical outcomes: An analysis of adults and adolescents with hypophosphatasia treated with asfotase alfa

BackgroundHypophosphatasia (HPP), a rare metabolic disease, can be inherited in an autosomal recessive (biallelic) or an autosomal dominant (monoallelic) manner. Most of the severe, early-onset, frequently lethal HPP in infants is acquired through recessive inheritance; less severe, later-onset, typically nonlethal HPP phenotypes are acquired through either dominant or recessive inheritance. HPP's variable clinical presentation arises from >400 identified ALPL pathogenic variants with likely variable penetrance, especially with autosomal dominant inheritance. This post hoc analysis investigated the relationship between ALPL variant state (biallelic and monoallelic) and clinical outcomes with asfotase alfa in HPP. MethodsData were pooled from two phase 2, randomized, open-label studies in adolescents and adults with HPP; one study evaluated the efficacy and safety of different doses of asfotase alfa (n = 25), and the other assessed the pharmacodynamics and safety of asfotase alfa (n = 19). Patients were grouped by ALPL variant state (biallelic or monoallelic). Available data from both studies included ALPL pathogenic variant state, Baseline characteristics, HPP-specific medical history, and Baseline TNSALP substrate levels (inorganic pyrophosphate [PPi] and pyridoxal 5′-phosphate [PLP]) concentrations). Clinical outcomes over 5 years of treatment were available from only the efficacy and safety study. ResultsIn total, 44 patients with known variant status were included in the pooled analysis (biallelic, n = 30; monoallelic, n = 14). The most common pathogenic variant was c.571G > A (p.Glu191Lys) in biallelic patients (allele frequency: 19/60) and c.1133A > T (p.Asp378Val) in monoallelic patients (allele frequency: 7/28). Median (min, max) Baseline PPi concentrations were significantly higher in patients with a biallelic vs monoallelic variant state (5.3 [2.2, 12.1] vs 4.3 [3.5, 7.4] μM; P = 0.0113), as were Baseline PLP concentrations (221.4 [62.4, 1590.0] vs 75.1 [28.8, 577.0] ng/mL; P= 0.0022). HPP-specific medical history was generally similar between biallelic and monoallelic patients in terms of incidence and type of manifestations; notable exceptions included fractures, which were more common among monoallelic patients, and delayed walking and bone deformities such as abnormally shaped chest and head and bowing of arms or legs, which were more common among biallelic patients. Data from the efficacy and safety study (n = 19) showed that median PPi and PLP concentrations were normalized over 5 years of treatment in patients with both variant states. Median % predicted distance walked on the 6-Minute Walk Test remained within the normal range for monoallelic patients over 4 years of treatment, and improved from below normal (<84%) to normal in biallelic patients. ConclusionsAlthough patients with biallelic variants had significantly higher Baseline PPi and PLP levels than monoallelic variants, both groups generally showed similar pretreatment Baseline clinical characteristics. Treatment with asfotase alfa for up to 5 years normalized TNSALP substrate concentrations and improved functional outcomes, with no clear differences between biallelic and monoallelic variant states. This study suggests that patients with HPP have significant disease burden, regardless of ALPL variant state.

Abstract PS10-05: Ribociclib + letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancer (ABC): Expanded safety analysis of the phase IIIb CompLEEment-1 trial

Abstract Background: CompLEEment-1 (NCT02941926) is an ongoing Phase IIIb trial of ribociclib (RIB) in combination with letrozole (LET) in the first-line setting for patients (pts) with HR+, HER2- ABC, reflecting a real-world clinical setting by including a more diverse pt population than those included in the pivotal MONALEESA trials. Here we report further analyses of the primary endpoint of safety from the completed Core Phase of the trial. Methods: CompLEEment-1 included women of any menopausal status and men with HR+, HER2- ABC treated with ≤1 line of prior chemotherapy and no prior hormonal therapy for advanced disease. Pts received RIB (600 mg QD, 3 weeks on/1 week off) in combination with LET (2.5 mg QD, continuous). Premenopausal women and men received a luteinizing hormone-releasing hormone agonist (3.6 mg goserelin or 7.5 mg leuprolide, Q28D). The primary endpoints were safety and tolerability. Updated analyses included dose reduction/interruption or treatment discontinuation due to adverse events (AEs), clinical impact of AEs of special interest (AESI), and exposure-adjusted incidence/occurrence rates (IRs) for AESI. Results: At data cutoff (November 8, 2019) 3,246 pts had been evaluated (median follow-up of 25.4 months), and median duration of exposure to RIB was 17.5 months; 1,301 (40.1%) pts completed Core Phase treatment, 415 of whom moved to the Extension Phase. Overall, 1,945 (59.9%) pts permanently discontinued treatment, mostly due to progressive disease (34.2%) and AEs (15.5%). Treatment-related AEs were reported in 3,091 (95.2%) pts, leading to dose modification in 2,235 (68.9%) pts. Dose modification occurred most often in pts with grade ≥3 neutropenia (dose interruption, 1,671 [51.5%] pts; dose reduction, 480 [14.8%] pts); treatment discontinuation occurred most frequently in pts with grade ≥3 increased alanine aminotransferase (ALT; 116 [3.6%] pts) or aspartate aminotransferase (AST; 68 [2.1%] pts). Grade ≥3 neutropenia occurred in 1,856 (57.2%) pts, with the median time to first occurrence of 4.1 weeks and median duration of first occurrence of 1.1 weeks. As measured by laboratory values, grade ≥2 increased ALT and AST occurred in 453 (14.0%) and 380 (11.7%) pts, respectively. Grade ≥2 QTcF prolongation was infrequent, occurring in 101 (3.1%) pts, leading 8 (0.2%) pts to discontinue from treatment. AESI rarely led to hospitalization (0 to 0.3%) and none were fatal. Exposure-adjusted IRs for AESI per 100 patient-years of exposure show that with increasing RIB exposure, the IR and the event rates for AESI decreased by a factor of ×2 to ×8 from 0-1 years compared with 1-2 years (Table 1). Conclusions: AEs associated with RIB + LET combination therapy were manageable, consistent with previous Phase III trials of RIB + LET - and adjusted IRs for AESI notably decreased from Year 1 to Year 2 of treatment. These data further support the use of RIB + LET for first-line treatment of HR+, HER2- ABC in both men and women of any menopausal status and in a broader and more diverse patient population. Table 1. Exposure-adjusted IRs for selected AESI per 100 patient-years of exposure0-1 years1-2 yearsAESIIR per 100 PTYaEvents per 100 PTYbIR per 100 PTYaEvents per 100 PTYbNeutropenia276.76410.2292.43200.83ALT increased20.3741.663.796.32AST increased17.5133.272.944.61QTcF prolongation8.4410.221.081.26aIR per 100 PTY: n/100 PTY, number of patients with an event divided by the corresponding sum of the exposure duration for patients, where duration of exposure in patient treatment-years (PTY) is counted up to the first qualifying event (or duration of exposure in time interval for patients without an event).bEvents per 100 PTY: n/100 PTY, number of events divided by the corresponding sum of the exposure duration, where duration of exposure in patient treatment-years (PTY) is duration of exposure in time interval. Citation Format: Janice Lu, Paul Cottu, Miguel Martín, Claudio Zamagni, Aleix Prat, Stephen Chia, Guy Jerusalem, Senthil Rajappa, Constanta Timcheva, Lyudmila Zhukova, Katie Zhou, Jiwen Wu, Lakshmi Menon-Singh, Michelino De Laurentiis. Ribociclib + letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancer (ABC): Expanded safety analysis of the phase IIIb CompLEEment-1 trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-05.