Mirikizumab Improves Quality of Life in Patients With Moderately-to-Severely Active Ulcerative Colitis: Results From the Phase 3 LUCENT-1 Induction and LUCENT-2 Maintenance Studies.

Background: Mirikizumab, an anti-IL-23p19 antibody, demonstrated efficacy in phase 3, randomized, double-blind, placebo-controlled LUCENT-1 (induction/NCT03518086) and LUCENT-2 (maintenance/NCT03524092) ulcerative colitis (UC) studies. We evaluated the effect of mirikizumab on quality-of-life (QoL) outcomes in these studies. Methods: In LUCENT-1, 1162 patients with moderately-to-severely active UC were randomized 3:1 to receive mirikizumab 300 mg intravenous or placebo every 4 weeks (Q4W) for 12 weeks. In LUCENT-2, mirikizumab induction responders (N = 544) were re-randomized 2:1 to receive mirikizumab 200 mg subcutaneous or placebo Q4W through week (W) 40 (W52 of treatment). QoL was assessed at W12 and W52 using patient-reported outcomes. Treatments were statistically compared using analysis of covariance model (continuous outcomes) and Cochran-Mantel-Haenszel test (binary outcomes). Results: At W12 and W52, mirikizumab showed significant improvement in Inflammatory Bowel Disease Questionnaire (IBDQ) total and domain scores (P < .001); 36-Item Short Form Health Survey (SF-36) Physical Component Summary (PCS), Mental Component Summary (MCS), and domain scores (P < .05); EQ-5D-5L scores (P < .001); Work Productivity and Activity Impairment Questionnaire (UC) scores (P < .05); Patient Global Rating of Severity (P < .001); and Patient Global Rating of Change (P < .01) scores. A significantly higher proportion of mirikizumab-treated patients achieved IBDQ response (W12: 72.7% vs 55.8%; W52: 79.2% vs 49.2%; P < .001), IBDQ remission (W12: 57.5% vs 39.8%; W52: 72.3% vs 43.0%; P < .001), and clinically important improvements in PCS (W12: 50.6% vs 41.5%; W52: 61.9% vs 36.9%; P < .01) and MCS (W12: 44.2% vs 37.8%; W52: 51.2% vs 34.6%; P < .05) scores. Conclusions: Mirikizumab improved QoL in patients with moderately-to-severely active UC in phase 3 LUCENT-1 and LUCENT-2 studies. Clinical trials registration number: LUCENT-1: NCT03518086; LUCENT-2: NCT03524092.

Real-World Biologic Adherence, Persistence, and Monotherapy Comparisons in US Patients with Psoriasis: Results from IBM MarketScan® Databases.

INTRODUCTION: Limited real-world data are available comparing multiple biologics on their adherence, persistence, and the use of concomitant biologics in the treatment of moderate-to-severe psoriasis in clinical practice. The objective was to compare persistence of and adherence to ixekizumab (IXE) treatment, as monotherapy or with concomitant medication, versus patients receiving other commonly prescribed biologics. METHODS: Patients who newly initiated IXE, adalimumab (ADA), etanercept (ETN), secukinumab (SEC), or ustekinumab (UST) in IBM MarketScan® databases with diagnosis of psoriasis were identified. Treatment comparisons on medication persistence, adherence, and monotherapy were based on balanced samples after inverse probability of treatment weighting (IPTW). RESULTS: A higher proportion of patients receiving IXE had had previous biologic therapies (50.3%) versus other biologics (ADA: 9.1%, ETN: 10.9%, SEC: 33.9%, UST: 19.7%). Patients treated with IXE showed statistically (p < 0.001) greater persistence than patients treated with SEC, ADA, UST, or ETN at both 1-year follow-up and up to 3 years of follow-up. Adherence for patients treated with IXE was significantly (p < 0.001) higher compared to ADA, ETN, and UST at both 1-year follow-up and up to 3 years of follow-up. There was no significantly higher adherence in patients treated with IXE compared to those treated with SEC at 1-year follow-up, but IXE had higher adherence than SEC (p < 0.05) at 1-3 year follow-up. IXE showed longer time on monotherapy than ADA (p < 0.001), ETN (p < 0.001), SEC (p < 0.05), and UST (p < 0.001) for both 1-year and 1-3 year follow-up. Sensitivity analyses on persistence, adherence, and monotherapy with further model adjustments after IPTW confirmed the findings. CONCLUSIONS: Patients treated with IXE were more persistent on and adherent to treatment and remained on monotherapy longer compared to those on all other commonly prescribed biologics combined or with individual biologics.

Sustained High Efficacy and Favorable Safety Over Five Years in Patients With Burdensome Psoriasis (UNCOVER-1/UNCOVER-2).

BACKGROUND: Long-term efficacy, safety, and quality of life with ixekizumab (IXE) through 5 years in UNCOVER-1 and UNCOVER-2 patients with baseline scalp, nail, or palmoplantar psoriasis were assessed. METHODS: Patients included in this intent-to-treat subanalysis had baseline involvement in at least one of the three anatomic areas (scalp, fingernail, or palmoplantar locations) and 1) received IXE through week 60, with a 160-mg starting dose 80 mg Q2W through week 12 and Q4W thereafter, 2) achieved a static Physician’s Global Assessment score of 0 or 1 at week 12, and 3) completed week 60 and continued treatment with IXE Q4W or were escalated to Q2W during the long-term extension. Efficacy outcomes (e.g., percent improvement in Psoriasis Scalp Severity Index [PSSI], Nail Psoriasis Severity Index [NAPSI], Palmoplantar Psoriasis Area and Severity [PPASI], and Dermatology Life Quality Index [DLQI]) were summarized by descriptive statistics through week 264. RESULTS: Patients rapidly achieved and sustained improvements in scalp, nail, and palmoplantar psoriasis for up to 5 years with IXE. Patients achieved complete clearance at year 5: observed (scalp, 82%; nail, 73%; palmoplantar, 96%) and mNRI (scalp, 77%; nail, 67%; palmoplantar, 85%). Up to 80% of patients reported DLQI 0,1 responses at week 12, which were sustained through week 264. No increases in the number of annual treatment-emergent adverse events were observed from years 1–5. CONCLUSION: Patients receiving IXE for 5 years sustained high rates of improvement in scalp, nail, and palmoplantar psoriasis, with a long-term quality of life benefit with no unexpected safety signals. J Drugs Dermatol. 2021;20(8):880-887. doi:10.36849/JDD.6101.

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.

OBJECTIVE: 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. METHODS: 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 60–264). 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). RESULTS: At week 264 in UNCOVER-1 and -2, the observed itch NRS ≥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. CONCLUSION: 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.

Clinical response beyond the Systemic Lupus Erythematosus Responder Index: post-hoc analysis of the BLISS-SC study.

OBJECTIVE: The Systemic Lupus Erythematosus (SLE) Responder Index (SRI), developed as a primary outcome measure for use in clinical trials, captures improvement in SLE disease activity without concomitant worsening in disease manifestations. This study investigated the relationships between the SRI and clinical/laboratory correlates of SRI response in patients with SLE. METHODS: This was a post-hoc analysis of the phase III, double-blind, placebo-controlled study of subcutaneous BeLimumab in Subjects with Systemic lupus erythematosus - SubCutaneous (BLISS-SC). Patients were randomised to weekly belimumab 200 mg subcutaneously or placebo, plus standard SLE therapy. Changes from baseline to week 52 in clinical and laboratory parameters were compared among SRI responders and non-responders, irrespective of the treatment received. RESULTS: SRI responders (n=475) had significantly better (p<0.0001) outcomes compared with non-responders (n=358), including (by definition) higher proportions achieving ≥4-point improvement in Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (100.0% vs 2.0%), no worsening in British Isles Lupus Assessment Group (BILAG; 0 new BILAG A or ≤1 new BILAG B score; 100.0 % vs 50.3%) and no worsening (<0.3-point increase) in Physician's Global Assessment score (100.0% vs 49.7%). Among patients receiving >7.5 mg/day corticosteroids at baseline, significantly more SRI responders had reductions in prednisone dose to ≤7.5 mg/day than non-responders. SRI responders reported lower flare rates and improvements in serological markers and Functional Assessment of Chronic Illness Therapy-Fatigue score than non-responders. CONCLUSION: SRI response is associated with improvements in clinical and laboratory measures, strengthening its value as a clinically meaningful primary endpoint in clinical trials.

Assessing attributes of topical vehicles for the treatment of acne, atopic dermatitis, and plaque psoriasis.

There is limited information available regarding patient preferences and attributes of topical product formulations for specific dermatologic conditions. This study focused on product attributes that were most desirable for 3 dermatologic conditions: acne, atopic dermatitis (AD), and plaque psoriasis (PP). Six focus groups were conducted with participants self-reporting 1 of these conditions and use of 2 or more topical treatments. Discussion focused on symptoms, treatments tried, and vehicle attributes. Fifty-four subjects participated: acne, n=19; AD, n=18; and PP, n=17. The most commonly reported prescription medication vehicles were creams and ointments, followed by lotions, gels, and foams. Itching and redness were the only symptoms spontaneously reported across all 6 focus groups. The attributes considered most important across all conditions included: moisturizing, absorbs/disappears/dries quickly, available in various formulations, does not bleach or stain skin/hair/clothing, is not greasy or oily, is not sticky or tacky, is long lasting/long acting, is fragrance or odor free, is easy to apply/simple to use, and can use all the time. Preferences attributable to acne included: easy to dispense/dispenses right amount, nondrying, product goes on/spreads smoothly, container is not easily broken/does not leak, and creamy. Preferences attributable to AD included: not noticeable to others/conceals area, good consistency, and cooling. Patient preference for product vehicle is relevant to adherence as compliance is a major factor for high rates of failure for dermatologic treatments.

A multicenter, randomized, double-blind study of the efficacy and safety of calcipotriene foam, 0.005%, vs vehicle foam in the treatment of plaque-type psoriasis of the scalp.

BACKGROUND: Calcipotriene ointment and cream are effective treatments for psoriasis, but many patients with scalp psoriasis prefer lighter, less messy vehicles. OBJECTIVES: To evaluate the efficacy and safety of calcipotriene foam, 0.005%, for plaque-type psoriasis of the scalp. METHODS: Subjects (n=363) were randomized into an 8-week, multicenter, double-blind, vehicle-controlled, parallel-group, phase 3b study of calcipotriene foam, 0.005% (NCT01139580). Primary end point was the proportion of subjects with an Investigator's Static Global Assessment (ISGA) score of 0 (clear) or 1 (almost clear) at week 8 for scalp involvement. Body involvement, target lesion score, and improvement for erythema, scaling, and plaque thickness were also assessed.
RESULTS: At week 8, more subjects in the calcipotriene foam, 0.005% group (40.9%) met the primary end point vs the vehicle foam group (24.2%; intent-to-treat [ITT] population; P <.001); a significant difference between groups was also observed at weeks 2 (P = .041) and 4 (P <.001). No significant difference was observed between treatment groups for ISGA of body psoriasis (ITT population; P = .544). In the per-protocol population, but not the ITT population, more subjects in the calcipotriene foam, 0.005%, group than the vehicle foam group met the secondary end points for scaling (P = .019) and plaque thickness (P =.027). Incidence of adverse events in both treatment groups was low; calcipotriene foam, 0.005%, was associated with erythema. LIMITATIONS: An 8-week study provides limited safety and efficacy data.
CONCLUSION: Calcipotriene foam, 0.005%, was more effective than vehicle foam for improving scalp psoriasis over an 8-week period, with improvements evident from week 2, and had a similar safety profile to vehicle foam.

A randomized, double-blind phase 4 study of the efficacy and safety of ethanol-free clobetasol propionate foam, 0.05%, vs vehicle foam in the treatment of chronic hand dermatitis.

BACKGROUND: Chronic hand dermatitis may have a significant detrimental effect on daily home-related and work-related activities, and quality of life (QOL). Clobetasol propionate foam, 0.05%, is indicated for the treatment of inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in patients aged 12 years and older. OBJECTIVES: To demonstrate superior efficacy, similar safety, and superior QOL outcomes in subjects with moderate to severe chronic hand dermatitis following treatment with clobetasol propionate foam, 0.05%, compared with vehicle foam. METHODS: In this randomized, double-blind, vehicle-controlled, parallel-group, multicenter study (ClinicalTrials.gov identifier NCT01323673), subjects aged 12 years and older with moderate to severe chronic hand dermatitis and an Investigator's Static Global Assessment (ISGA) score of 3 or 4 at baseline were randomized 1:1 to receive clobetasol propionate foam, 0.05%, or vehicle foam, twice daily over 15 days. The primary end point was the proportion of subjects who achieved treatment success, defined as improvement from baseline of ≥ 2 ISGA grades for the target hand at day 15. RESULTS: In total, 125 subjects were enrolled: 62 subjects were randomized to the clobetasol propionate foam group and 63 subjects were randomized to the vehicle foam group. The proportion of subjects with treatment success at day 15 did not differ significantly between treatment groups. Adverse events (AEs) were reported in 18% of subjects in the clobetasol propionate foam group and 8% of subjects in the vehicle foam group. No serious AEs, AEs resulting in discontinuation of study product, or severe AEs were reported in the clobetasol propionate foam group. CONCLUSIONS: Clobetasol propionate foam, 0.05%, was not significantly more efficacious than vehicle foam at improving chronic hand dermatitis on investigator-assessed end points. Emollient properties of the study product vehicle may be a confounder in the study.

Effect of bipolar electrode spacing on phrenic nerve stimulation and left ventricular pacing thresholds: an acute canine study.

BACKGROUND: Phrenic nerve stimulation (PNS) is a common complication of cardiac resynchronization therapy when left ventricular (LV) pacing occurs via a coronary vein. The purpose of this study was to evaluate the effects of bipolar electrode spacing on PNS and LV pacing thresholds. METHODS AND RESULTS: Electrophysiology catheters with standard (2 mm-5 mm-2 mm) or modified (1 mm-5 mm-1 mm) interelectrode spacing was, respectively, inserted in a posterior/lateral cardiac vein in a randomized order in 6 anesthetized dogs via jugular access. The phrenic nerve was dissected via a left minithoracotomy and repositioned over the vein as close as possible to one of the electrodes. The presence of PNS was verified (ie, PNS threshold <2 V at 0.5 ms in unipolar configuration). Bipolar pacing was delivered using the electrode closest to the phrenic nerve as the cathode, and multiple bipolar electrode spacing configurations were tested. During bipolar pacing, PNS threshold increased as bipolar electrode spacing was reduced (P<0.05), whereas LV pacing thresholds did not change significantly (P>0.05). Compared with a standard bipolar electrode spacing of 20 mm for LV leads, 1 and 2 mm bipolar electrode spacing resulted in a PNS threshold increase of 5.5±2.2 V (P=0.003) and 2.8±1.7 V (P<0.001), respectively. Similarly, PNS threshold increased by 6.5±3.7 V with 1 mm and by 3.8±1.9 V with 2 mm bipolar pacing (both P<0.001), compared with unipolar pacing. CONCLUSIONS: This study suggests that reducing LV bipolar electrode spacing from the standard 20 mm to 1 or 2 mm may significantly increase the PNS threshold without compromising LV pacing thresholds.

Acute effects of His bundle pacing versus left ventricular and right ventricular pacing on left ventricular function.

Dual-chamber pacing with His bundle pacing has theoretical advantages over conventional right ventricular (RV) apical pacing. We compared indexes of left ventricular (LV) function during acute dual-chamber pacing from the His bundle and other RV and LV pacing sites. Twelve patients (6 men; 63 +/- 11 years) with a standard indication for electrophysiologic study were included. Average QRS duration was 100 +/- 19 ms. Ejection fraction was 48 +/- 15%. A pressure-volume catheter was positioned in the left ventricle through the femoral arterial access. Pressure-volume loops were collected during atrial (AAI) and dual-chamber overdrive pacing at 82 +/- 15 beats/min after 2 minutes of hemodynamic stabilization. Ventricular pacing catheter position was randomized between the RV apex, RV septal, and free wall portions of the outflow tract, LV free wall, and His bundle. His bundle capture was verified from surface electrocardiographic morphometry using standard criteria. Atrioventricular delay was set to the P wave-His duration -10 ms to minimize the effects of fusion (96 +/- 22 ms). LV only pacing, but not His pacing, resulted in improved stroke work and stroke volume compared with alternate site RV pacing. No changes in +dP/dt, LV end-systolic pressure. LV end-diastolic pressure, or cycle efficiency, were observed between RV pacing sites. In conclusion, acute His bundle pacing did not improve LV function compared with alternate site RV pacing and may be inferior to LV pacing.

Ventricular pacing lead location alters systemic hemodynamics and left ventricular function in patients with and without reduced ejection fraction.

OBJECTIVES: We compared left ventricular (LV) systolic and diastolic function during right ventricular (RV), LV, and biventricular (BiV) pacing in patients with narrow QRS duration with and without LV dysfunction. BACKGROUND: The optimal RV pacing lead location for patients with a standard indication for ventricular pacing remains controversial. METHODS: Left ventricular pressure and volume data were determined via conductance catheter during electrophysiology study in 31 patients divided into groups with ejection fraction (EF) > or =40% (n = 17) or EF <40% (n = 14). QRS duration was 91 +/- 18 versus 106 +/- 25 ms, respectively (p = NS). Hemodynamic data were recorded during atrial and dual chamber pacing from the RV apex, RV free wall, RV septum, LV free wall, and BiV. RESULTS: In patients with EF > or =40%, RV pacing at 1 or more sites, but not LV free wall or BiV pacing, significantly (p < 0.05) impaired cardiac output (CO), stroke work (SW), EF, and LV relaxation compared with atrial overdrive pacing. Right ventricular pacing also impaired hemodynamics and LV function in patients with EF <40%. However, LV and BiV pacing increased CO, SW, EF, and LV +dP/dt(MAX) in patients with LV dysfunction. Left ventricular and BiV pacing enhanced an index of global LV cycle efficiency in patients with depressed EF. The detrimental hemodynamic effects of RV pacing were attenuated by selecting the optimal RV pacing site. CONCLUSIONS: Right ventricular pacing worsens LV function in patients with and without LV dysfunction unless the RV pacing site is optimized. Left ventricular and BiV pacing preserve LV function in patients with EF >40% and improve function in patients with EF <40% despite no clinical indication for BiV pacing.