Least-squares Mean Reductions Research Articles

Work Productivity and General Health Through 2 Years of Guselkumab Treatment in a Phase 3 Randomized Trial of Patients With Active Psoriatic Arthritis.

To evaluate the effect of guselkumab on work productivity and nonwork daily activity impairment and general health status through 2years in patients who were biologic-naïve with active psoriatic arthritis (PsA) in the phase 3 DISCOVER-2 clinical trial. Adult patients with PsA were randomized to subcutaneous injections of guselkumab 100mg every 4weeks (Q4W); at weeks 0, 4, then every 8 weeks (Q8W); or placebo (throughweek 24 with crossoverto guselkumab Q4W). Work productivity and nonwork daily activity impairment were assessed using the Work Productivity and Activity Impairment Questionnaire for PsA (WPAI-PsA) and patient-reported general health status using the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Index and EQ-Visual Analog Scale (EQ-VAS). Least-squares (LS) mean changes from baseline in WPAI-PsA domains and EQ-5D-5L/EQ-VAS were assessed through week 100. Changes in employment status were utilized to estimate potential indirect savings from improved work productivity. Of 739 randomized patients, 738 had available baseline data for the analyses (Q4W 245; Q8W 248; placebo 245). At week 24, greater improvements in work productivity, nonwork daily activity, and EQ-5D-5L/EQ-VAS were observed in the Q4W and Q8W groups versus the placebo group. At week 100, LS mean reductions in work productivity impairment (- 23.8% to - 28.0%) and nonwork daily activity impairment (- 26.6% to - 29.2%) and improvements in EQ-5D-5L/EQ-VAS (0.14 to 0.15/21.2 to 25.0) were maintained in patients receiving guselkumab. Among patients employed at baseline, 12.1-16.4% were not employed at week 100, and 20.0-25.3% shifted from not employed at baseline to employed at week 100. Potential yearly indirect cost savings (USD) from improved work productivity at week 100 ranged from $16,529 to $19,409. Patients with active PsA treated with guselkumab demonstrated reduced impairment in work productivity and nonwork daily activity, together with improvement in general health status and substantial potential cost savings, over a 2-year period. Clinicaltrials.gov identifier: NCT03158285.

Effectiveness and Safety of iGlarLixi (Insulin Glargine 100U/mL Plus Lixisenatide) in Type2 Diabetes According to the Timing of Daily Administration: Data from the REALI Pooled Analysis.

iGlarLixi (insulin glargine 100U/mL plus lixisenatide) has demonstrated glycaemic efficacy and safety in adults with inadequately controlled type2 diabetes mellitus (T2DM). Per the European Medicines Agency's product label, iGlarLixi should be injected once a day within 1h prior to a meal, preferably the same meal every day when the most convenient meal has been chosen. It is however unknown whether iGlarLixi administration timing affects glycaemic control and safety, as clinical trial evidence is mainly based on pre-breakfast iGlarLixi administration. Therefore, we assessed the effectiveness and safety of iGlarLixi in clinical practice, according to its administration timing. Data were pooled from two prospective observational studies including 1303 European participants with T2DM inadequately controlled on oral antidiabetic drugs with or without basal insulin who initiated iGlarLixi therapy for 24weeks. Participants were classified into four subgroups based on daily timing of iGlarLixi injection: pre-breakfast (N = 436), pre-lunch (N = 262), pre-dinner (N = 399), and those who switched iGlarLixi injection time during the study (N = 206). No meaningful differences in baseline characteristics were observed between the study groups. Least-squares mean reductions in haemoglobinA1c (HbA1c) from baseline to week24 were substantial in all groups, with the numerically largest decrease observed in the pre-breakfast group (1.57%) compared with the pre-lunch (1.27%), pre-dinner (1.42%), or changed injection time (1.33%) groups. Pre-breakfast iGlarLixi injection also resulted in a numerically greater proportion of participants achieving HbA1c < 7.0% at week24 (33.7% versus 19.0% for pre-lunch, 25.6% pre-dinner, and 23.2% changed injection time). iGlarLixi was well tolerated across all groups, with low rates of gastrointestinal disorders and hypoglycaemia. Mean body weight decreased similarly in all groups (by 1.3-2.3kg). iGlarLixi was effective and safe regardless of its daily administration time. However, pre-breakfast iGlarLixi injection resulted in a more effective glycaemic control.

Lumasiran for Advanced Primary Hyperoxaluria Type 1: Phase 3 ILLUMINATE-C Trial

Lumasiran reduces urinary and plasma oxalate (POx) in patients with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. ILLUMINATE-C evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of lumasiran in patients with PH1 and advanced kidney disease. Phase 3, open-label, single-arm trial. Multinational study; enrolled patients with PH1 of all ages, estimated glomerular filtration rate≤45 mL/min/1.73 m2 (if age≥12 months) or increased serum creatinine level (if age<12 months), and POx≥20 μmol/L at screening, including patients with or without systemic oxalosis. Lumasiran administered subcutaneously; 3 monthly doses followed by monthly or quarterly weight-based dosing. Primary end point: percent change in POx from baseline to month 6 (cohort A; not receiving hemodialysis at enrollment) and percent change in predialysis POx from baseline to month 6 (cohort B; receiving hemodialysis at enrollment). Pharmacodynamic secondary end points: percent change in POx area under the curve between dialysis sessions (cohort B only); absolute change in POx; percent and absolute change in spot urinary oxalate-creatinine ratio; and 24-hour urinary oxalate adjusted for body surface area. All patients (N= 21; 43% female; 76% White) completed the 6-month primary analysis period. Median age at consent was 8 (range, 0-59) years. For the primary end point, least-squares mean reductions in POx were 33.3% (95% CI,-15.2% to 81.8%) in cohort A (n= 6) and 42.4% (95% CI, 34.2%-50.7%) in cohort B (n= 15). Improvements were also observed in all pharmacodynamic secondary end points. Most adverse events were mild or moderate. No patient discontinued treatment or withdrew from the study. The most commonly reported lumasiran-related adverse events were injection-site reactions, all of which were mild and transient. Single-arm study without placebo control. Lumasiran resulted in substantial reductions in POx with acceptable safety in patients with PH1 who have advanced kidney disease, supporting its efficacy and safety in this patient population. Alnylam Pharmaceuticals. Registered at ClinicalTrials.gov with study number NCT04152200 and at EudraCT with study number 2019-001346-17. Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by excessive hepatic oxalate production that frequently causes kidney failure. Lumasiran is an RNA interference therapeutic that is administered subcutaneously for the treatment of PH1. Lumasiran has been shown to reduce oxalate levels in the urine and plasma of patients with PH1 who have relatively preserved kidney function. In the ILLUMINATE-C study, the efficacy and safety of lumasiran were evaluated in patients with PH1 and advanced kidney disease, including a cohort of patients undergoing hemodialysis. During the 6-month primary analysis period, lumasiran resulted in substantial reductions in plasma oxalate with acceptable safety in patients with PH1 complicated by advanced kidney disease.

FC054: Voclosporin for Lupus Nephritis: Results of the Two-Year Aurora 2 Continuation Study

Abstract BACKGROUND AND AIMS Voclosporin, a novel calcineurin inhibitor, was approved in the USA in January 2021 for the treatment of adult patients with active lupus nephritis in combination with background immunosuppressive therapy. Voclosporin has a favorable metabolic profile and a consistent dose-concentration relationship, eliminating the need for therapeutic drug monitoring. Previously reported results from the Phase 2 AURA-LV and Phase 3 AURORA 1 studies showed that the addition of voclosporin to mycophenolate mofetil (MMF) and low-dose steroids in patients with lupus nephritis significantly increased rates of complete renal response at 48 weeks (AURA-LV) and 52 weeks (AURORA 1). Here we report the results of the completed continuation study, AURORA 2, which assessed the long-term safety and tolerability of voclosporin compared with placebo in patients with lupus nephritis receiving treatment for an additional 24 months following completion of the AURORA 1 study. METHOD Key inclusion criteria for the parent AURORA 1 study included a diagnosis of biopsy-proven active lupus nephritis (Class III, IV, or V ± III/IV), proteinuria ≥ 1.5 mg/mg (≥2 mg/mg for Class V) and estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2. Patients who completed AURORA 1 were eligible to enroll in AURORA 2 and continued with the same blinded treatment of voclosporin (23.7 mg BID) or placebo in combination with MMF (target dose 2 g/day) and low-dose oral steroids. Safety and tolerability were evaluated by monitoring adverse events and laboratory assessments including eGFR; changes in urine protein creatinine ratio (UPCR) were also assessed. RESULTS In total, 116 patients in the voclosporin arm and 100 patients in the control arm enrolled in AURORA 2, with 92 (79.3%) and 73 (73.0%) patients in each respective arm completing treatment to the end of AURORA 2. There were no new or unexpected safety signals detected in patients who continued on treatment with voclosporin compared to control-treated patients. Rates of serious adverse events in the voclosporin (19.0%) and control arms (24.0%) were similar, with eight serious adverse events of infection in each arm. Estimated glomerular filtration rate remained stable through the end of AURORA 2 (Figure 1). The slopes of the least-squares (LS) mean change in corrected eGFR from AURORA 2 baseline to end of study were –0.2 [95% confidence interval (CI) –3.0 to 2.7' in the voclosporin arm and –5.4 (95% CI –8.4 to –2.3) in the control arm. There were no deaths in the voclosporin arm during AURORA 2; four deaths were reported in the control arm due to pulmonary embolism (n = 1) and coronavirus infection (n = 3). The LS mean reductions in UPCR observed in AURORA 1 were maintained in AURORA 2 with no increase in UPCR noted at the follow-up visit 4 weeks after study drug discontinuation (Figure 2). CONCLUSION Voclosporin was well-tolerated over three years of treatment with a similar safety profile to control and no unexpected safety signals detected. Further, the significant and meaningful reductions in proteinuria initially achieved in AURORA 1 were maintained throughout AURORA 2. These data provide evidence of a long-term treatment benefit of voclosporin in patients with lupus nephritis.

FC070: Lumasiran for Patients with Primary Hyperoxaluria Type 1 with Impaired Kidney Function: Data from the 6-Month Analysis of the Phase 3 Illuminate-C Trial

Abstract BACKGROUND AND AIMS Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder characterised by hepatic oxalate overproduction that leads to progressive kidney disease. As kidney function declines, oxalate elimination is compromised and plasma oxalate (POx) increases, leading to systemic oxalosis. In chronic kidney disease (CKD) stages 3b–5, elevated POx is directly related to the pathophysiology of oxalosis, and reduction of POx is a relevant clinical trial endpoint. Lumasiran, an RNA interference therapeutic designed to reduce hepatic oxalate production, is indicated for the treatment of PH1 in all age groups. Data from the ILLUMINATE-C trial (EudraCT: 2019–0 013 346-17) demonstrated substantial reductions in POx and acceptable safety in patients with PH1 with impaired kidney function, including patients on haemodialysis (HD), who received lumasiran for 6 months. In Cohorts A (no HD) and B (on HD), respectively, lumasiran led to 33.33% [95% confidence interval (95% CI): −15.16 to 81.82] and 42.43% (95% CI: 34.15–50.71) least-squares (LS) mean reductions in POx from baseline to Month 6 (the primary endpoint). Here, we present METHOD ILLUMINATE-C is an ongoing Phase 3, single-arm study with two cohorts, Cohort A (N = 6; no HD at study start) and Cohort B (N = 15; on HD). The 6-month primary analysis period is followed by an extension period (EP) of up to 54 months. Key inclusion criteria include genetically confirmed PH1, eGFR ≤ 45 mL/min/1.73 m2 and POx ≥ 20 μmol/L. Patients received weight-based dosing of subcutaneous lumasiran. Outcomes of interest for the current analysis included assessments of cardiac oxalosis using echocardiography, medullary nephrocalcinosis by kidney ultrasound, kidney stone events and burdensome symptoms of PH1. RESULTS All 21 patients [43% female; 76% white; median age 8 (range 0–59) years] completed the 6-month primary analysis period. Among patients with abnormal left ventricular ejection fraction (LVEF; abnormal defined as LVEF &amp;lt; 55%) at baseline, 1/1 patient in Cohort A and 2/4 patients in Cohort B showed ≥ 5% improvement at Month 6. Among patients with abnormal global longitudinal strain (GLS, a measure of LV contractility more sensitive than LVEF for predicting outcomes; abnormal defined as |GLS| &amp;lt;15%) at baseline, 1/1 patient in Cohort A and 3/3 patients in Cohort B showed ≥ 2% improvement at Month 6. In Cohort A, 5/6 patients had nephrocalcinosis at baseline, 2 remained stable, none worsened, and 3 improved (2 unilateral and 1 bilateral improvement) at Month 6. In Cohort A, 1 patient did not have nephrocalcinosis at baseline and had bilateral worsening at Month 6. In Cohort B, 2/11 patients had nephrocalcinosis at baseline; both improved (1 unilateral and 1 bilateral improvement). In Cohort A, the rate of kidney stone events per person-year was 3.20 (95% CI: 1.96–5.22) in the 12 months prior to consent and 1.48 (95% CI: 0.55–3.92) during the first 6 months of lumasiran treatment. For patients in both cohorts, the most burdensome symptoms at baseline, including fatigue, nausea/decreased appetite, bone pain and decreased mobility, improved or remained stable at Month 6; none of the symptoms worsened. CONCLUSION Lumasiran treatment resulted in substantial reductions in POx in patients of all ages with PH1 and advanced kidney disease. The observations regarding cardiac measures that reflect systemic oxalosis, together with the kidney stone event and nephrocalcinosis results, are consistent with mobilisation of oxalate from systemic stores. Data on these long-term outcomes will continue to be collected and further evaluated in the EP. These results, along with previous reports from ILLUMINATE-A and ILLUMINATE-B, provide evidence supporting the effectiveness of lumasiran across the full spectrum of patients affected by PH1.

Phase 3 trial of lumasiran for primary hyperoxaluria type 1: A new RNAi therapeutic in infants and young children

PurposePrimary hyperoxaluria type 1 (PH1) is a rare, progressive, genetic disease with limited treatment options. We report the efficacy and safety of lumasiran, an RNA interference therapeutic, in infants and young children with PH1. MethodsThis single-arm, open-label, phase 3 study evaluated lumasiran in patients aged <6 years with PH1 and an estimated glomerular filtration rate >45 mL/min/1.73 m2, if aged ≥12 months, or normal serum creatinine, if aged <12 months. The primary end point was percent change in spot urinary oxalate to creatinine ratio (UOx:Cr) from baseline to month 6. Secondary end points included proportion of patients with urinary oxalate ≤1.5× upper limit of normal and change in plasma oxalate. ResultsAll patients (N = 18) completed the 6-month primary analysis period. Median age at consent was 50.1 months. Least-squares mean percent reduction in spot UOx:Cr was 72.0%. At month 6, 50% of patients (9/18) achieved spot UOx:Cr ≤1.5× upper limit of normal. Least-squares mean percent reduction in plasma oxalate was 31.7%. The most common treatment-related adverse events were transient, mild, injection-site reactions. ConclusionLumasiran showed rapid, sustained reduction in spot UOx:Cr and plasma oxalate and acceptable safety in patients aged <6 years with PH1, establishing RNA interference therapies as safe, effective treatment options for infants and young children.

Efficacy and Safety of Dapagliflozin in Heart Failure With Reduced Ejection Fraction According to N-Terminal Pro-B-Type Natriuretic Peptide: Insights From the DAPA-HF Trial.

Effective therapies for HFrEF usually reduce NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, and it is important to establish whether new treatments are effective across the range of NT-proBNP. We evaluated both these questions in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial. Patients in New York Heart Association functional class II to IV with a left ventricular ejection fraction ≤40% and a NT-proBNP level ≥600 pg/mL (≥600 ng/L; ≥400 pg/mL if hospitalized for HF within the previous 12 months or ≥900 pg/mL if atrial fibrillation/flutter) were eligible. The primary outcome was the composite of an episode of worsening HF or cardiovascular death. Of the 4744 randomized patients, 4742 had an available baseline NT-proBNP measurement (median, 1437 pg/mL [interquartile range, 857-2650 pg/mL]). Compared with placebo, treatment with dapagliflozin significantly reduced NT-proBNP from baseline to 8 months (absolute least-squares mean reduction, -303 pg/mL [95% CI, -457 to -150 pg/mL]; geometric mean ratio, 0.92 [95% CI, 0.88-0.96]). Dapagliflozin reduced the risk of worsening HF or cardiovascular death, irrespective of baseline NT-proBNP quartile; the hazard ratio for dapagliflozin versus placebo, from lowest to highest quartile was 0.43 (95% CI, 0.27-0.67), 0.77 (0.56-1.04), 0.78 (0.60-1.01), and 0.78 (0.64-0.95); P for interaction=0.09. Consistent benefits were observed for all-cause mortality. Compared with placebo, dapagliflozin increased the proportion of patients with a meaningful improvement (≥5 points) in Kansas City Cardiomyopathy Questionnaire total symptom score (P for interaction=0.99) and decreased the proportion with a deterioration ≥5 points (P for interaction=0.87) across baseline NT-proBNP quartiles. In patients with HFrEF, dapagliflozin reduced NT-proBNP by 300 pg/mL after 8 months of treatment compared with placebo. In addition, dapagliflozin reduced the risk of worsening HF and death, and improved symptoms, across the spectrum of baseline NT-proBNP levels included in DAPA-HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.

Efficacy and safety of fremanezumab for chronic migraine prevention: Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in Japanese and Korean patients.

ObjectiveTo determine the efficacy and safety of fremanezumab administration in Japanese and Korean patients with chronic migraine (CM).BackgroundAvailable preventive treatments for CM are limited by various efficacy and safety issues. Fremanezumab, a monoclonal antibody that targets the calcitonin gene‐related peptide pathway involved in migraine pathogenesis, has been shown to be effective and well tolerated in large‐scale, international Phase 3 trials.MethodsRandomized, placebo‐controlled trial of patients with CM who received subcutaneous fremanezumab monthly (675 mg at baseline and 225 mg at weeks 4 and 8), fremanezumab quarterly (675 mg at baseline and placebo at weeks 4 and 8), or matching placebo. Primary endpoint was the mean change from baseline in the monthly (28‐day) average number of headache days of at least moderate severity during the 12 weeks after the first dose.ResultsAmong 571 patients randomized (safety set, n = 569; full analysis set, n = 566), the least‐squares mean (±standard error [SE]) reduction in the average number of headache days of at least moderate severity per month during 12 weeks was significantly greater with fremanezumab monthly (–4.1 ± 0.4) and fremanezumab quarterly (–4.1 ± 0.4) than with placebo (–2.4 ± 0.4). The difference from the placebo group in the mean change (95% confidence interval [CI]) was −1.7 days (−2.54, −0.80) for the fremanezumab monthly group and −1.7 days (−2.55, −0.82) for the fremanezumab quarterly group (p < 0.001 vs. placebo for both fremanezumab groups). The percentage of patients with a ≥50% reduction in the average number of headache days of at least moderate severity per month (response rate) was higher with fremanezumab monthly (29.0%) and fremanezumab quarterly (29.1%) than with placebo (13.2%) in addition to other improvements in secondary endpoints, including reduction of acute medication use (mean change from baseline during 12‐week period ± SE: fremanezumab monthly, –3.7 ± 0.4; fremanezumab quarterly, –3.9 ± 0.4; placebo, –2.4 ± 0.4) and improvements in disability scores (mean change from baseline in six‐item Headache Impact Test score at 4 weeks after third injection ± SE: fremanezumab monthly, –8.1 ± 0.7; fremanezumab quarterly, –8.0 ± 0.7; placebo, –6.5 ± 0.7). Fremanezumab was well tolerated with a similar incidence of adverse events including injection‐site reactions as placebo (patients with at least one treatment‐emergent adverse event: fremanezumab total, n = 232 [61.4%]; placebo, n = 118 [61.8%]).ConclusionFremanezumab effectively prevents CM in Japanese and Korean patients and was well tolerated. No safety signal was detected.

Efficacy and safety of fremanezumab for episodic migraine prevention: Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in Japanese and Korean patients.

ObjectiveTo evaluate the efficacy and safety of two dosing regimens of fremanezumab in Japanese and Korean patients with episodic migraine.BackgroundEpisodic migraine, which accounts for more than 90% of migraine cases, is inadequately addressed by widely available preventive therapies. Fremanezumab, a monoclonal antibody that selectively targets the trigeminal sensory neuropeptide calcitonin gene‐related peptide involved in migraine pathogenesis, has demonstrated efficacy in international Phase 3 trials of patients with both chronic and episodic migraine.MethodsThis Phase 3 randomized, placebo‐controlled trial randomly assigned patients with episodic migraine to receive subcutaneous fremanezumab monthly (225 mg at baseline, week 4, and week 8), fremanezumab quarterly (675 mg at baseline and placebo at weeks 4 and 8), or matching placebo. The primary endpoint was the mean change from baseline in the monthly average number of migraine days during the 12‐week treatment period after the first dose.ResultsOf 357 patients enrolled (safety set, n = 356; full analysis set, n = 354), the least‐squares mean (±standard error) reductions in the average number of migraine days per month during 12 weeks were significantly greater with fremanezumab monthly (−4.0 ± 0.4, n = 121) and fremanezumab quarterly (−4.0 ± 0.4, n = 117) than with placebo (−1.0 ± 0.4, n = 116; p < 0.0001 for both comparisons). The proportion of patients reaching at least a 50% reduction in the monthly average number of migraine days during the 12‐week period after initial administration was also significantly improved with fremanezumab (fremanezumab monthly, 41.3%; fremanezumab quarterly, 45.3%; placebo, 11.2%; p < 0.0001 for both comparisons) as were other secondary endpoints (p < 0.001 for all comparisons between fremanezumab and placebo). Injection‐site reactions were more common in fremanezumab‐treated patients (fremanezumab monthly, 25.6%; fremanezumab quarterly, 29.7%; placebo, 21.4%).ConclusionFremanezumab prevents episodic migraine in Japanese and Korean patients to a similar extent than in previously reported populations with no new safety concerns.

Efficacy of three disinfectant formulations and a hydrogen peroxide/silver fogging system on surfaces experimentally inoculated with meticillin-resistant Staphylococcus pseudintermedius.

Effective environmental disinfection is necessary to prevent nosocomial infections from meticillin-resistant Staphylococcus pseudintermedius (MRSP). However, there are currently no commercial disinfectant sprays or fogging systems with label claims against MRSP. To evaluate the efficacy of a quaternary ammonium product (QAC), an accelerated hydrogen peroxide product (AHP), a hydrogen peroxide and silver product (HAL), and a hydrogen peroxide and silver fogging system (FOG) against MRSP. Sterile plastic surfaces inoculated with MRSP were treated with 200µL of QAC, AHP or HAL for the recommended contact times. For FOG, inoculated samples were placed in eight positions within a sealed room before fogging for the recommended contact time. Post-treatment bacterial counts were compared to untreated positive controls. Sterile uninoculated surfaces served as negative controls. Least-squares mean reduction (log10 ) in colony forming units (cfu) was 3.55 log10 for QAC (P<0.0001), 3.60 log10 for AHP (P<0.0001), 1.66 log10 for HAL (P<0.0001) and 0.32 log10 for FOG (P=0.004). QAC, AHP and HAL reduced MRSP cfu by 99.97%, 99.98% and 97.81%, respectively. FOG reduced cfu by 52.14%. QAC and AHP effectively disinfected surfaces inoculated with MRSP. Although HAL provided lower MRSP reduction, it may be considered clinically acceptable. FOG as a sole means of MRSP disinfection was not supported yet may have utility as an adjunctive disinfectant in clinical areas with bacterial densities lower than our experimental inoculum.

PRO65 INDIRECT COMPARISON BETWEEN HUMAN C1-INHIBITOR (C1-INH) SUBCUTANEOUS TREATMENT AND LANADELUMAB FOR ROUTINE PREVENTION OF HEREDITARY ANGIOEDEMA (HAE) ATTACKS

For prophylaxis of HAE attacks, approved therapies include C1 Esterase Inhibitor Subcutaneous (Human) [C1-INH(SC)] replacement and lanadelumab, a monoclonal antibody. In the absence of a head-to-head comparative study of the two treatments, an indirect comparison of data from two independent clinical trials was undertaken. Two phase 3 multicenter, randomized, double-blind, placebo-controlled, trials were identified which evaluated either lanadelumab (the HELP study; NCT02586805; 26 weeks; parallel-group) or C1-INH(SC) (the COMPACT study; NCT01912456; 2x16-week periods; crossover) for routine prevention of HAE attacks. To standardize differences in design and methodology, COMPACT individual patient data were re-analyzed using Poisson regression as in HELP. Estimates (95% CI) for the monthly attack rate reduction over placebo were compared to HELP published results. Treatment group, period, sequence and normalized run-in period attack rates were used as model fixed effects. The original COMPACT model-based mean (95% CI) HAE attack rate for the recommended C1-INH(SC) 60 IU/kg twice weekly and the placebo sequences were 0.52 (0.00, 1.04) and 4.03 (3.51, 4.55), respectively. The HELP model-based mean HAE attack rates for the lanadelumab treatment arms (150mg q4weeks, 300mg q4weeks, 300mg q2weeks) and the placebo arm were 0.48 (0.31, 0.73), 0.53 (0.36, 0.77), 0.26 (0.14, 0.46) and 1.97 (1.64, 2.36), respectively. The HELP least-squares mean reduction in attack rates over placebo were 1.49 (1.08, 1.90); 1.44 (1.04, 1.84), and 1.71 (1.33, 2.09), respectively, compared to the HELP-model-based (Poisson regression) COMPACT reduction of 3.29 (2.65, 3.98) attacks per month. HELP-model- based COMPACT results confirm that the strong efficacy of C1-INH (SC) is invariant to the statistical method used.

138 Efficacy and Safety of SEP-363856, a Novel Psychotropic Agent with a Non-D2 Mechanism of Action, in the Treatment of Schizophrenia

SEP-363856 is a novel psychotropic agent that has shown broad efficacy in animal models of schizophrenia and depression. Its antipsychotic effects appear to be mediated by agonist activity at both trace amine-associated receptor 1 (TAAR1) and 5-HT1A receptors. Notably, SEP-363856 does not bind to any dopaminergic, serotonergic (except 5-HT1A), glutamatergic, or other neuroreceptors thought to mediate the effects of currently available antipsychotics. The aim of this study was to evaluate the efficacy and safety of SEP-363856 in acutely symptomatic patients with schizophrenia. Patients aged 18-40 years meeting DSM-5 criteria for schizophrenia (PANSS total score ≥80) were randomized, double-blind, to 4-weeks of flexible-dose SEP-363856 (50 or 75 mg/d) or placebo. Efficacy measures included the Positive and Negative Syndrome Scale (PANSS) total score (primary), PANSS subscale scores, and the Clinical Global Impressions-Severity (CGI-S) score. Change from baseline in primary and secondary measures were analyzed using a mixed model for repeated measures (MMRM) analysis. Study treatment groups were similar at baseline: SEP-363856 (N=120; male, 64.2%; mean age, 30.0 years; PANSS total score, 101.4) and placebo (N=125; male, 63.2%; mean age, 30.6 years; PANSS total score, 99.7). Least-squares (LS) mean reduction from baseline to week 4 was significantly greater for SEP-363856 vs. placebo on the PANSS total score (-17.2 vs. -9.7; P=0.001; effect size, 0.45), PANSS positive subscale score (-5.5 vs. -3.9; P=0.019; effect size, 0.32), PANSS negative subscale score (-3.1 vs. -1.6; P=0.008; effect size, 0.37), PANSS general psychopathology subscale score (-9.0 vs. -4.7; P<0.001; effect size, 0.51), and the CGI-Severity score (-1.0 vs. -0.5; P<0.001; effect size, 0.52). Discontinuation rates for SEP-363856 vs. placebo were similar overall (21.7% vs. 20.8%) and due to an adverse event (8.3% vs. 6.4%). Change in weight, lipids, glucose and prolactin was similar in SEP-363856 and placebo groups. Adverse events occurring with an incidence ≥2% on SEP-363856 or placebo (with SEP-363856 incidence higher than placebo) were: somnolence (6.7% vs. 4.8%), agitation (5.0% vs. 4.8%), nausea (5.0% vs. 3.2%), diarrhea (2.5% vs. 0.8%), and dyspepsia (2.5% vs. 0%). The proportion of patients who reported any extrapyramidal symptom was 3.3% on SEP-363856 and 3.2% on placebo. In this placebo-controlled study, treatment with SEP-363856, a novel psychotropic agent, was associated with statistically significant and clinically meaningful improvement in schizophrenia symptoms as demonstrated by endpoint change in PANSS total and subscale scores, and CGI-Severity scores. Safety and tolerability findings for SEP-363856 were in general similar to placebo. In particular, SEP-363856 was not associated with extrapyramidal symptoms, akathisia, or hyperprolactinemia, consistent with its non-D2 mechanism of action. NCT02969382. Supported by funding from Sunovion Pharmaceuticals Inc.

Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials

Post-partum depression is associated with substantial morbidity, and improved pharmacological treatment options are urgently needed. We assessed brexanolone injection (formerly SAGE-547 injection), a positive allosteric modulator of γ-aminobutyric-acid type A (GABAA) receptors, for the treatment of moderate to severe post-partum depression. We did two double-blind, randomised, placebo-controlled, phase 3 trials, at 30 clinical research centres and specialised psychiatric units in the USA. Eligible women were aged 18-45 years, 6 months post partum or less at screening, with post-partum depression and a qualifying 17-item Hamilton Rating Scale for Depression (HAM-D) score (≥26 for study 1; 20-25 for study 2). Women with renal failure requiring dialysis, anaemia, known allergy to allopregnanolone or to progesterone, or medical history of schizophrenia, bipolar disorder, or schizoaffective disorder were excluded. Patients were randomly assigned (1:1:1) to receive a single intravenous injection of either brexanolone 90 μg/kg per h (BRX90), brexanolone 60 μg/kg per h (BRX60), or matching placebo for 60 h in study 1, or (1:1) BRX90 or matching placebo for 60 h in study 2. Patients, the study team, site staff, and the principal investigator were masked to treatment allocation. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all patients who started infusion of study drug or placebo, had a valid HAM-D baseline assessment, and had at least one post-baseline HAM-D assessment. The safety population included all randomised patients who started infusion of study drug or placebo. Patients were followed up until day 30. The trials have been completed and are registered with ClinicalTrials.gov, numbers NCT02942004 (study 1) and NCT02942017 (study 2). Participants were enrolled between Aug 1, 2016, and Oct 19, 2017, in study 1, and between July 25, 2016, and Oct 11, 2017, in study 2. We screened 375 women simultaneously across both studies, of whom 138 were randomly assigned to receive either BRX90 (n=45), BRX60 (n=47), or placebo (n=46) in study 1, and 108 were randomly assigned to receive BRX90 (n=54) or placebo (n=54) in study 2. In study 1, at 60 h, the least-squares (LS) mean reduction in HAM-D total score from baseline was 19·5 points (SE 1·2) in the BRX60 group and 17·7 points (1·2) in the BRX90 group compared with 14·0 points (1·1) in the placebo group (difference -5·5 [95% CI -8·8 to -2·2], p=0·0013 for the BRX60 group; -3·7 [95% CI -6·9 to -0·5], p=0·0252 for the BRX90 group). In study 2, at 60 h, the LS mean reduction in HAM-D total score from baseline was 14·6 points (SE 0·8) in the BRX90 group compared with 12·1 points (SE 0·8) for the placebo group (difference -2·5 [95% CI -4·5 to -0·5], p=0·0160). In study 1, 19 patients in the BRX60 group and 22 patients in the BRX90 group had adverse events compared with 22 patients in the placebo group. In study 2, 25 patients in the BRX90 group had adverse events compared with 24 patients in the placebo group. The most common treatment-emergent adverse events in the brexanolone groups were headache (n=7 BRX60 group and n=6 BRX90 group vs n=7 placebo group for study 1; n=9 BRX90 group vs n=6 placebo group for study 2), dizziness (n=6 BRX60 group and n=6 BRX90 group vs n=1 placebo group for study 1; n=5 BRX90 group vs n=4 placebo group for study 2), and somnolence (n=7 BRX60 group and n=2 BRX90 group vs n=3 placebo group for study 1; n=4 BRX90 group vs n=2 placebo group for study 2). In study 1, one patient in the BRX60 group had two serious adverse events (suicidal ideation and intentional overdose attempt during follow-up). In study 2, one patient in the BRX90 group had two serious adverse events (altered state of consciousness and syncope), which were considered to be treatment related. Administration of brexanolone injection for post-partum depression resulted in significant and clinically meaningful reductions in HAM-D total score at 60 h compared with placebo, with rapid onset of action and durable treatment response during the study period. Our results suggest that brexanolone injection is a novel therapeutic drug for post-partum depression that has the potential to improve treatment options for women with this disorder. Sage Therapeutics, Inc.

Efficacy and effectiveness of valsartan/amlodipine and valsartan/amlodipine/hydrochlorothiazide in hypertension: randomized controlled versus observational studies

Objective: The aim of this post-hoc analysis was to compare the results from randomized controlled trials (RCTs) and real-world evidence (RWE) studies of valsartan/amlodipine (Val/Aml) and valsartan/amlodipine/hydrochlorothiazide (Val/Aml/HCTZ) in patients with uncontrolled hypertension (>140/90 mmHg).Methods: Data was pooled from 15 RCTs (N = 5542) and 8 RWE studies (N = 1397) for Val/Aml; and 2 RCTs (N = 804) and 5 RWE studies (N = 9380) for Val/Aml/HCTZ. Patients who received Val/Aml (80/5, 160/5, 160/10, 320/5, or 320/10 mg), Val/Aml/HCTZ (160/5/12.5, 160/5/25, 160/10/12.5, 160/10/25, or 320/10/25 mg) or placebo were considered for this analysis. Only patients with both baseline and follow-up assessment within 60–90 days after baseline had been included in the analysis. Patients with missing values were excluded from the analysis. Using fitted linear mixed-effects model and random factors, treatment interactions and study design with mean sitting systolic blood pressure (msSBP), diastolic BP (msDBP) and pulse pressure (msPP) reductions from baseline to Week 8–12 of treatment were compared.Results: Baseline demographics and patient characteristics were comparable between RCT and RWE datasets and within Val/Aml and Val/Aml/HCTZ treatment groups. In both RCT and RWE studies, least-squares mean (LSM) reduction in msSBP/msDBP and msPP from baseline were significant (p < .05) across all dosages. The efficacy of Val/Aml in RCTs was statistically significantly greater than in RWE studies for msSBP/msDBP (−23.1/−13.8 vs. −17.9/-9.1 mmHg) but the difference was non-significant for msPP (−8.6 vs. −9.3 mmHg; p = .77). For Val/Aml/HCTZ, no direct comparison was available but a similar trend was observed. The difference observed for msSBP and msDBP may be due to routine practice setting, larger populations may have more confounders and different behaviors towards treatment adherence.Conclusion: These findings demonstrate that the efficacy of Val/Aml and Val/Aml/HCTZ in RCTs was more pronounced compared with their effectiveness in RWE studies in different ethnic populations although the overall benefit was not different.

Fremanezumab for the Preventive Treatment of Chronic Migraine

BackgroundFremanezumab, a humanized monoclonal antibody targeting calcitonin gene–related peptide (CGRP), is being investigated as a preventive treatment for migraine. We compared two fremanezumab dose regimens with placebo for the prevention of chronic migraine.MethodsIn this phase 3 trial, we randomly assigned patients with chronic migraine (defined as headache of any duration or severity on ≥15 days per month and migraine on ≥8 days per month) in a 1:1:1 ratio to receive fremanezumab quarterly (a single dose of 675 mg at baseline and placebo at weeks 4 and 8), fremanezumab monthly (675 mg at baseline and 225 mg at weeks 4 and 8), or matching placebo. Both fremanezumab and placebo were administered by means of subcutaneous injection. The primary end point was the mean change from baseline in the average number of headache days (defined as days in which headache pain lasted ≥4 consecutive hours and had a peak severity of at least a moderate level or days in which acute migraine–specific medication [triptans or ergots] was used to treat a headache of any severity or duration) per month during the 12 weeks after the first dose.ResultsOf 1130 patients enrolled, 376 were randomly assigned to fremanezumab quarterly, 379 to fremanezumab monthly, and 375 to placebo. The mean number of baseline headache days (as defined above) per month was 13.2, 12.8, and 13.3, respectively. The least-squares mean (±SE) reduction in the average number of headache days per month was 4.3±0.3 with fremanezumab quarterly, 4.6±0.3 with fremanezumab monthly, and 2.5±0.3 with placebo (P<0.001 for both comparisons with placebo). The percentage of patients with a reduction of at least 50% in the average number of headache days per month was 38% in the fremanezumab-quarterly group, 41% in the fremanezumab-monthly group, and 18% in the placebo group (P<0.001 for both comparisons with placebo). Abnormalities of hepatic function occurred in 5 patients in each fremanezumab group (1%) and 3 patients in the placebo group (<1%).ConclusionsFremanezumab as a preventive treatment for chronic migraine resulted in a lower frequency of headache than placebo in this 12-week trial. Injection-site reactions to the drug were common. The long-term durability and safety of fremanezumab require further study. (Funded by Teva Pharmaceuticals; ClinicalTrials.gov number, NCT02621931.)

Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol

BackgroundIn a previous study, a single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in low-density lipoprotein (LDL) cholesterol levels over the course of 84 days in healthy volunteers.MethodsWe conducted a phase 2, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial of inclisiran administered as a subcutaneous injection in patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels. Patients were randomly assigned to receive a single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran. The primary end point was the change from baseline in LDL cholesterol level at 180 days. Safety data were available through day 210, and data on LDL cholesterol and proprotein convertase subtilisin–kexin type 9 (PCSK9) levels were available through day 240.ResultsA total of 501 patients underwent randomization. Patients who received inclisiran had dose-dependent reductions in PCSK9 and LDL cholesterol levels. At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo). The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180. At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran.ConclusionsIn our trial, inclisiran was found to lower PCSK9 and LDL cholesterol levels among patients at high cardiovascular risk who had elevated LDL cholesterol levels. (Funded by the Medicines Company; ORION-1 ClinicalTrials.gov number, NCT02597127.)

A Highly Durable RNAi Therapeutic Inhibitor of PCSK9

BackgroundInclisiran (ALN-PCSsc) is a long-acting RNA interference (RNAi) therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin–kexin type 9 (PCSK9), a target for the lowering of low-density lipoprotein (LDL) cholesterol.MethodsIn this phase 1 trial, we randomly assigned healthy volunteers with an LDL cholesterol level of at least 100 mg per deciliter in a 3:1 ratio to receive a subcutaneous injection of inclisiran or placebo in either a single-ascending-dose phase (at a dose of 25, 100, 300, 500, or 800 mg) or a multiple-dose phase (125 mg weekly for four doses, 250 mg every other week for two doses, or 300 or 500 mg monthly for two doses, with or without concurrent statin therapy); each dose cohort included four to eight participants. Safety, the side-effect profile, and pharmacodynamic measures (PCSK9 level, LDL cholesterol level, and exploratory lipid variables) were evaluated.ResultsThe most common adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea. All the adverse events were mild or moderate in severity. There were no serious adverse events or discontinuations due to adverse events. There was one grade 3 elevation in the γ-glutamyltransferase level, which was considered by the investigator to be related to statin therapy. In the single-dose phase, inclisiran doses of 300 mg or more reduced the PCSK9 level (up to a least-squares mean reduction of 74.5% from baseline to day 84), and doses of 100 mg or more reduced the LDL cholesterol level (up to a least-squares mean reduction of 50.6% from baseline). Reductions in the levels of PCSK9 and LDL cholesterol were maintained at day 180 for doses of 300 mg or more. All multiple-dose regimens reduced the levels of PCSK9 (up to a least-squares mean reduction of 83.8% from baseline to day 84) and LDL cholesterol (up to a least-squares mean reduction of 59.7% from baseline to day 84).ConclusionsIn this phase 1 trial, no serious adverse events were observed with inclisiran. Doses of 300 mg or more (in single or multiple doses) significantly reduced levels of PCSK9 and LDL cholesterol for at least 6 months. (Funded by Alnylam Pharmaceuticals and the Medicines Company; ClinicalTrials.gov number, NCT02314442.)

Safety and Efficacy of Omarigliptin (MK-3102), a Novel Once-Weekly DPP-4 Inhibitor for the Treatment of Patients With Type 2 Diabetes

This study was conducted to determine the optimal dose of omarigliptin, a once-weekly (q.w.) dipeptidyl peptidase IV (DPP-4) inhibitor, for the treatment of patients with type 2 diabetes and evaluate the long-term safety of that dose. In a multicenter, double-blind, 12-week, dose-range finding study, 685 oral antihyperglycemic agent-naïve or washed-out subjects with type 2 diabetes were randomized to one of five once-weekly doses of omarigliptin (0.25 mg, 1 mg, 3 mg, 10 mg, or 25 mg) or placebo. The primary efficacy end point was change from baseline in HbA1c, and secondary end points were 2-h postmeal glucose (PMG) and fasting plasma glucose (FPG). Analysis included all patients who received at least one dose of the study medication. Subjects who completed the base study were eligible to enter a 66-week extension study. Once-weekly treatment for 12 weeks with omarigliptin provided dose-related reductions in HbA1c, 2-h PMG, and FPG. At week 12, the omarigliptin 25-mg dose provided the greatest glycemic efficacy. The placebo-adjusted least-squares mean reductions from baseline in HbA1c, 2-h PMG, and FPG were -0.72% (-7.8 mmol/mol), -2.5, and -1.3 mmol/L, respectively (all P < 0.001). The incidence of adverse events was similar across dose groups, with a low incidence of symptomatic hypoglycemia and no effect on body weight. Omarigliptin was generally well-tolerated throughout the base and extension studies. Omarigliptin 25 mg q.w., compared with placebo, provided significant glucose lowering and was generally well tolerated for up to 78 weeks in patients with type 2 diabetes.

Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial

Dulaglutide and liraglutide, both glucagon-like peptide-1 (GLP-1) receptor agonists, improve glycaemic control and reduce weight in patients with type 2 diabetes. In a head-to-head trial, we compared the safety and efficacy of once-weekly dulaglutide with that of once-daily liraglutide in metformin-treated patients with uncontrolled type 2 diabetes. We did a phase 3, randomised, open-label, parallel-group study at 62 sites in nine countries between June 20, 2012, and Nov 25, 2013. Patients with inadequately controlled type 2 diabetes receiving metformin (≥1500 mg/day), aged 18 years or older, with glycated haemoglobin (HbA1c) 7·0% or greater (≥53 mmol/mol) and 10·0% or lower (≤86 mmol/mol), and body-mass index 45 kg/m(2) or lower were randomly assigned to receive once-weekly dulaglutide (1·5 mg) or once-daily liraglutide (1·8 mg). Randomisation was done according to a computer-generated random sequence with an interactive voice response system. Participants and investigators were not masked to treatment allocation. The primary outcome was non-inferiority (margin 0·4%) of dulaglutide compared with liraglutide for change in HbA1c (least-squares mean change from baseline) at 26 weeks. Safety data were collected for a further 4 weeks' follow-up. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01624259. We randomly assigned 599 patients to receive once-weekly dulaglutide (299 patients) or once-daily liraglutide (300 patients). 269 participants in each group completed treatment at week 26. Least-squares mean reduction in HbA1c was -1·42% (SE 0·05) in the dulaglutide group and -1·36% (0·05) in the liraglutide group. Mean treatment difference in HbA1c was -0·06% (95% CI -0·19 to 0·07, pnon-inferiority<0·0001) between the two groups. The most common gastrointestinal adverse events were nausea (61 [20%] in dulaglutide group vs 54 [18%] in liraglutide group), diarrhoea (36 [12%] vs 36 [12%]), dyspepsia (24 [8%] vs 18 [6%]), and vomiting (21 [7%] vs 25 [8%]), with similar rates of study or study drug discontinuation because of adverse events between the two groups (18 [6%] in each group). The hypoglycaemia rate was 0·34 (SE 1·44) and 0·52 (3·01) events per patient per year, respectively, and no severe hypoglycaemia was reported. Once-weekly dulaglutide is non-inferior to once-daily liraglutide for least-squares mean reduction in HbA1c, with a similar safety and tolerability profile. Eli Lilly and Company.

A 52-Week Placebo-Controlled Trial of Evolocumab in Hyperlipidemia

BackgroundEvolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in phase 2 studies. We conducted a phase 3 trial to evaluate the safety and efficacy of 52 weeks of treatment with evolocumab.MethodsWe stratified patients with hyperlipidemia according to the risk categories outlined by the Adult Treatment Panel III of the National Cholesterol Education Program. On the basis of this classification, patients were started on background lipid-lowering therapy with diet alone or diet plus atorvastatin at a dose of 10 mg daily, atorvastatin at a dose of 80 mg daily, or atorvastatin at a dose of 80 mg daily plus ezetimibe at a dose of 10 mg daily, for a run-in period of 4 to 12 weeks. Patients with an LDL cholesterol level of 75 mg per deciliter (1.9 mmol per liter) or higher were then randomly assigned in a 2:1 ratio to receive either evolocumab (420 mg) or placebo every 4 weeks. The primary end point was the percent change from baseline in LDL cholesterol, as measured by means of ultracentrifugation, at week 52.ResultsAmong the 901 patients included in the primary analysis, the overall least-squares mean (±SE) reduction in LDL cholesterol from baseline in the evolocumab group, taking into account the change in the placebo group, was 57.0±2.1% (P<0.001). The mean reduction was 55.7±4.2% among patients who underwent background therapy with diet alone, 61.6±2.6% among those who received 10 mg of atorvastatin, 56.8±5.3% among those who received 80 mg of atorvastatin, and 48.5±5.2% among those who received a combination of 80 mg of atorvastatin and 10 mg of ezetimibe (P<0.001 for all comparisons). Evolocumab treatment also significantly reduced levels of apolipoprotein B, non–high-density lipoprotein cholesterol, lipoprotein(a), and triglycerides. The most common adverse events were nasopharyngitis, upper respiratory tract infection, influenza, and back pain.ConclusionsAt 52 weeks, evolocumab added to diet alone, to low-dose atorvastatin, or to high-dose atorvastatin with or without ezetimibe significantly reduced LDL cholesterol levels in patients with a range of cardiovascular risks. (Funded by Amgen; DESCARTES ClinicalTrials.gov number, NCT01516879.)