Treating moderate-to-severe menopausal vasomotor symptoms with fezolinetant: analysis of responders using pooled data from two phase 3 studies (SKYLIGHT 1 and 2).

OBJECTIVES: The aims of the study were to further characterize the efficacy of fezolinetant for the treatment of moderate-to-severe vasomotor symptoms (VMS) due to menopause using responder analysis and to investigate whether efficacy, not adjusted for placebo, resulted in clinically meaningful within-patient change. METHODS: This prespecified analysis used pooled data from two phase 3, randomized, double-blind, placebo-controlled studies (SKYLIGHT 1 and 2). Responders were those experiencing ≥50%, ≥75%, ≥90%, or 100% reduction in VMS frequency from baseline to weeks 4 and 12. Responder analysis was performed for patient-reported outcome (PRO) measures to evaluate participants achieving a clinically meaningful within-patient change (not placebo adjusted) at week 4 and 12 versus baseline. Single responders were based on outcomes of VMS frequency, Patient-Reported Outcomes Measurement Information System Sleep Disturbance-Short Form 8b Total Score, Menopause-Specific Quality of Life (MENQoL) Total Score, and MENQoL VMS Domain Score. Double and triple responder analyses combined VMS frequency plus one or more of the PRO. Patient Global Impression of Change VMS was deemed a suitable anchor measure for meaningful within-patient change in VMS frequency. RESULTS: A greater proportion of fezolinetant-treated versus placebo-treated participants had ≥50%, ≥75%, ≥90%, or 100% reduction in VMS frequency from baseline to weeks 4 and 12. A greater proportion of responders were observed in the fezolinetant groups versus placebo at week 12 in all four single responder analyses. In the double and triple responder analyses, odds ratios were supportive of a beneficial effect for both doses of fezolinetant versus placebo. CONCLUSIONS: Fezolinetant was associated with significantly higher within-patient clinically meaningful improvement in important PRO, including VMS frequency, PROMIS SD SF 8b Total Score, MENQoL Total Score, and MENQoL VMS Domain Score.

Long-Term Outcomes with Prolonged-Release Tacrolimus in Kidney Transplantation: A Retrospective Real-World Data Analysis.

BACKGROUND Long-term real-world outcomes data for kidney transplant recipients (KTRs) converting from immediate-release tacrolimus (IRT) to prolonged-release tacrolimus (PRT) are limited. MATERIAL AND METHODS A retrospective, non-interventional review of adult KTRs treated with PRT for ≥1 month was conducted in Germany. Data were extracted from time of transplant (2008-2014) to 2018. Primary composite endpoints (graft loss, biopsy-confirmed acute rejection, graft dysfunction) and secondary endpoints (all-cause mortality, kidney function course, and tacrolimus dose/trough levels) were analyzed for sub-cohorts: de novo PRT, early conversion from IRT (within 6 months post-transplant), and late conversion (7 months to 3 years). RESULTS Analysis included 163 patients (101 de novo, 12 early converters, and 50 late converters). The overall Kaplan-Meier estimate of freedom from efficacy failure through 5 years was 0.537, (95% confidence interval (CI) 0.455-0.612) (de novo: 0.512 [0.407-0.608]; early converters: 0.500 [0.208-0.736]; late converters: 0.594 [0.443-0.717]). The overall survival rate was 0.925 (95% CI 0.872-0.957) (de novo: 0.900 [0.823-0.945]; early converters: 0.917 [0.539-0.988]; late converters: 0.977 [0.846-0.997]). During follow-up, there was a gradual reduction in tacrolimus dose and trough levels; kidney function remained stable in all cohorts. Multivariable analysis found re-transplantation, organ donor quality, best estimated glomerular filtration rate 8-12 weeks after transplant, and treatment center (between-center differences in age, sex, donor status/quality) were significantly associated with efficacy failure. CONCLUSIONS There was no difference in long-term survival profiles between KTRs who received PRT de novo vs those who converted from IRT, with 5-year survival remaining high in both groups.

Fezolinetant impact on health-related quality of life for vasomotor symptoms due to the menopause: Pooled data from SKYLIGHT 1 and SKYLIGHT 2 randomised controlled trials.

OBJECTIVE: To assess the effect of fezolinetant treatment on health-related quality of life using pooled data from SKYLIGHT 1 and 2 studies. DESIGN: Prespecified pooled analysis. SETTING: USA, Canada, Europe; 2019-2021. POPULATION: 1022 women aged ≥40 to ≤65 years with moderate-to-severe vasomotor symptoms (VMS; minimum average seven hot flushes/day), seeking treatment for VMS. METHODS: Women were randomised to 12-week double-blind treatment with once-daily placebo or fezolinetant 30 or 45 mg. Completers entered a 40-week, active extension (those receiving fezolinetant continued that dose; those receiving placebo re-randomised to fezolinetant received 30 or 45 mg). MAIN OUTCOME MEASURES: Mean changes from baseline to weeks 4 and 12 on Menopause-Specific Quality of Life (MENQoL) total and domain scores, Work Productivity and Activity Impairment questionnaire specific to VMS (WPAI-VMS) domain scores, Patient Global Impression of Change in VMS (PGI-C VMS); percentages achieving PGI-C VMS of 'much better' (PGI-C VMS responders). Mean reduction was estimated using mixed model repeated measures analysis of covariance. RESULTS: Fezolinetant 45 mg mean reduction over placebo in MENQoL total score was -0.57 (95% confidence interval [CI] -0.75 to -0.39) at week 4 and -0.47 (95% CI -0.66 to -0.28) at week 12. Reductions were similar for 30 mg. MENQoL domain scores were also reduced and WPAI-VMS scores improved. Twice as many women receiving fezolinetant reported VMS were 'much better' than placebo based on PGI-C VMS assessment. CONCLUSIONS: Fezolinetant treatment was associated with improvement in overall QoL, measured by MENQoL, and work productivity, measured by WPAI-VMS. A high proportion receiving fezolinetant felt VMS were 'much better' based on PGI-C VMS responder analysis.

Real-Life Anemia Management Among Patients with Non-Dialysis-Dependent Chronic Kidney Disease in Three European Countries.

Background: Anemia is prevalent among patients with chronic kidney disease (CKD), yet current evidence indicates that treatment may not adhere to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. We aimed to document the management of patients with non-dialysis-dependent (NDD)-CKD receiving erythropoiesis-stimulating agent (ESA) therapy in Europe. Methods: This retrospective, observational study extracted information from medical records in Germany, Spain, and the UK. Eligible patients were adults with NDD-CKD stages 3b-5 who initiated ESA therapy for anemia between January and December 2015. Anemia was defined as hemoglobin (Hb) <13.0 g/dL (males) or <12.0 g/dL (females). Data regarding ESA treatment, treatment response, concomitant iron therapy and blood transfusions were extracted up to 24 months post-ESA initiation, and data on CKD progression until abstraction date. Results: Eight hundred and forty-eight medical records were abstracted. Approximately 40% received no iron therapy prior to ESA initiation. At ESA initiation, mean ± standard deviation Hb level was 9.8 ± 1.0 g/dL. Most patients received darbepoetin alfa, and switching between ESAs was rare (8.5% of patients). Concomitant intravenous and oral iron therapy was prescribed for 36% and 42% of patients, respectively, during initial ESA therapy. Mean Hb levels reached the target level (10-12 g/dL) within 3-6 months of ESA initiation. Hb, transferrin saturation, and ferritin levels were infrequently monitored from 3 months post-ESA initiation. Rates of blood transfusion, dialysis, and diagnosis of end-stage renal disease were 16.4%, 19.3%, and 24.6%, respectively. Rates of kidney transplant and death were 4.8% and 8.8%, respectively. Conclusion: Among ESA-treated patients, ESA initiation was in accordance with KDIGO guidelines, but subsequent monitoring of Hb and iron deficiency were suboptimal.

Efficacy of Prolonged-release Tacrolimus After Conversion From Immediate-release Tacrolimus in Kidney Transplantation: A Retrospective Analysis of Long-term Outcomes From the ADMIRAD Study.

Prolonged-release tacrolimus (PRT) may offer improved outcomes after kidney transplantation compared with immediate-release tacrolimus (IRT). However, data on outcomes beyond 5-y posttransplantation are lacking. Methods: A retrospective, noninterventional chart review study examined long-term graft survival in adult kidney transplant participants in the Adherence Measurement in Stable Renal Transplant Patients Following Conversion From Prograf to Advagraf (ADMIRAD) clinical trial at 4 Belgian sites. Patients were randomized to receive once-daily PRT or twice-daily IRT for 6 mo, followed by treatment as per real-world clinical practice. Data were collected retrospectively from randomization day until December 31, 2018. Primary endpoints included efficacy failure, defined as a composite endpoint of graft loss, biopsy-confirmed acute rejection, and graft dysfunction. Secondary endpoints included overall patient survival and course of kidney function. Results: This analysis included 78.5% of patients from ADMIRAD (n = 108 PRT; n = 64 IRT). The Kaplan-Meier survival rate without efficacy failure from randomization to year 5 was 0.741 (95% confidence interval [CI]: 0.647, 0.813) for the PRT group (n = 80), and 0.667 (95% CI: 0.536, 0.768) for the IRT group (n = 42) and remained higher for PRT throughout 10 y follow-up (P = 0.041). The Kaplan-Meier estimate of overall survival from the time of last transplant was 0.981 (95% CI: 0.928, 0.995) and 0.880 (95% CI: 0.802, 0.928) at 5 and 10 y in the PRT group. Kidney function parameters and tacrolimus trough levels remained stable over the follow-up period. Conclusions: Patients in the ADMIRAD study who received PRT for up to 10 y had improved long-term outcomes compared with patients receiving IRT, with a consistent effect on both graft and patient survival.

Prevalence, severity, and associated factors in women in East Asia with moderate-to-severe vasomotor symptoms associated with menopause.

OBJECTIVE: To understand prevalence, severity, impact, and treatment of vasomotor symptoms associated with menopause, using cross-sectional survey data. METHODS: This online, two-part survey was conducted in East Asia among women 40-65 years recruited from established online panels (Edelman, Beijing; Hankook Research, Seoul; Rakuten Insight, Taipei) using stratified sampling. Part I collected demographics/disease characteristics, including menopausal status and vasomotor symptom severity. Women with moderate-to-severe vasomotor symptoms completed Part II, including clinical characteristics, health-related quality of life, and healthcare-seeking behavior. Primary endpoints included vasomotor symptom prevalence and severity and proportions of women eligible and willing to take hormone therapy. Results are presented for each of the three online panels separately and as a pooled total. All analyses are descriptive with no formal hypothesis testing across groups. RESULTS: Numbers of peri- versus postmenopausal women completing Part I were Edelman, 1,588 (55.1% vs 44.9%); Hankook Research, 1,000 (43.6% vs 56.4%); Rakuten Insight, 773 (61.7% vs 38.3%). Vasomotor symptom prevalence was =80% in each region; overall moderate-to-severe vasomotor symptom prevalence was 55%; >50% of women were untreated. Most of those treated used non-prescription treatments. Menopausal hormone therapy use was reported by 11.6% of peri- and 7.2% of postmenopausal women. In peri- and postmenopausal women with moderate-to-severe vasomotor symptoms, 8.6% and 3.4%, respectively, were hormone therapy-willing, 19.3% and 16.8% hormone therapy-contraindicated, 25.4% and 23.0% hormone therapy-cautious, and 10.2% and 8.3% hormone therapy-averse. Women experienced significant burden on health-related quality of life and substantial impairment of work productivity and daily activities. CONCLUSIONS: Vasomotor symptoms associated with menopause affected =80% of women aged 40 to 65 years. A substantial proportion of women are unsuitable for, or choose not to take, menopausal hormone therapy, resulting in an unmet need for nonhormonal treatment options.

Immunogenicity and safety of omalizumab in pre-filled syringes in patients with allergic (IgE-mediated) asthma.

BACKGROUND: Omalizumab, a humanised anti-immunoglobulin E monoclonal antibody for treatment of uncontrolled moderate-to-severe or severe persistent allergic asthma, was developed as a lyophilised powder for reconstitution. A liquid formulation in pre-filled syringes has now been developed. The purpose of this study was to assess the immunogenicity and safety of this liquid formulation. METHODS: In this multinational, open-label, single-arm study, patients (≥12 years) with moderate-to-severe allergic asthma were treated for 24 weeks with the liquid formulation of omalizumab (75 or 150 mg in a pre-filled syringe) at 2 or 4 week intervals. Immunogenicity was assessed by measurement of human anti-therapeutic antibody (ATA) levels. Safety was assessed by monitoring adverse events (AEs), haematology, blood chemistry, urine analysis and vital signs. RESULTS: A total of 155 patients were enrolled in the study. No patient had a confirmed positive ATA test result. Most frequent individual AEs were asthma (17.4%), sinusitis (17.4%) and upper respiratory tract infection (11.6%). Fourteen patients (9.0%) had serious AEs and there was one death (not treatment related). There were no cases of anaphylaxis according to Sampson criteria. Most patients remained within normal ranges for haematology and biochemistry laboratory variables. CONCLUSIONS: Omalizumab in pre-filled syringes was not associated with immunogenicity. This novel formulation, which does not require reconstitution, had a safety profile consistent with the lyophilised formulation. A limitation of this study is that efficacy of omalizumab in the treatment of asthma was not specifically addressed herein. Clinicaltrials.gov identifier: NCT00500539.

Omalizumab and the risk of malignancy: results from a pooled analysis.

BACKGROUND: Since initial registration, the omalizumab clinical trial database has expanded considerably, with a doubling of patients exposed in the clinical trial environment. Previous pooled data (2003) from phase I to III studies of omalizumab showed a numeric imbalance in malignancies arising in omalizumab recipients (0.5%) compared with control subjects (0.2%). The previous analysis was based on limited available data, warranting further investigation. OBJECTIVE: We sought to examine the incidence of malignancy using comprehensive pooled data from clinical trials of omalizumab-treated patients. METHODS: This pooled analysis included data from 67 phase I to IV clinical trials. The prespecified primary analysis assessed the incidence of primary malignancy in 32 randomized, double-blind, placebo-controlled (RDBPC) trials. RESULTS: There were 11,459 unique patients in all clinical trials (7,789 received omalizumab). The primary analysis identified malignancies in 25 patients (RDBPC trials): 14 in 4,254 omalizumab-treated patients and 11 in 3,178 placebo-treated patients. Incidence rates per 1,000 patient-years of observation time for omalizumab- and placebo-treated patients were 4.14 (95% CI, 2.26-6.94) and 4.45 (95% CI, 2.22-7.94), respectively; the corresponding rate ratio was 0.93 (95% CI, 0.39-2.27). Primary malignancies were of varying histologic type and occurred in a number of different organ systems; no cluster of histologies was identified. CONCLUSIONS: In this pooled analysis no association was observed between omalizumab treatment and risk of malignancy in RDBPC trials; the rate ratio was below unity. The data suggest that a causal relationship between omalizumab therapy and malignancy is unlikely.

Asthma symptom re-emergence after omalizumab withdrawal correlates well with increasing IgE and decreasing pharmacokinetic concentrations.

BACKGROUND: Physicians have questioned whether omalizumab can be discontinued or the dose reduced after clinical improvement is seen in patients with severe asthma. OBJECTIVES: To examine the relationships among omalizumab, free IgE, and clinical outcomes in a randomized, placebo-controlled trial in patients with severe persistent allergic asthma following a posology based on pretreatment total IgE and body weight. METHODS: A pharmacokinetic-pharmacodynamic binding model was used to calculate free IgE, omalizumab, and total IgE concentrations during the 28-week treatment and 16-week follow-up of the INvestigation of Omalizumab in seVere Asthma TrEatment (INNOVATE) study. These were plotted against the mean changes in the total asthma symptom score, morning peak expiratory flow, and rescue medication use for physician-defined treatment responders and nonresponders. RESULTS: The model accurately fitted omalizumab and free and total IgE, allowing reconstruction of the entire time course for each patient. Free IgE was rapidly suppressed below the 50 ng/mL (20.8 IU/mL) target, although there was a notable period before clinical measures stabilized. After treatment cessation, free IgE and omalizumab returned toward baseline and, after a delay, asthma symptoms re-emerged. Model-derived omalizumab and free IgE concentrations correlated well with changes in clinical outcomes, particularly in omalizumab-treated responders. Asthma symptoms exhibited different correlations during response onset compared with response offset (hysteresis), indicative of physiological time delays between changes in IgE levels and pulmonary function. CONCLUSION: Omalizumab and free IgE correlated well with clinical symptoms. Reducing omalizumab doses below those in the dosing table cannot be recommended; the resulting increase in free IgE would cause a deterioration in asthma control.