Weekly Semaglutide vs. Liraglutide Efficacy Profile: A Network Meta-Analysis

Introduction: Glucagon-like peptide 1 receptor agonist (GLP-1 RA) is a class of hypoglycemic medications. Semaglutide once-weekly (QW) and liraglutide once-daily (OD) significantly improved glycemic control compared to placebo. To date, no long-term phase III trials directly comparing semaglutide and liraglutide are available. This network meta-analysis (NMA) aims to compare the long-term efficacy of semaglutide and liraglutide. Methods: PubMed, Embase, and Cochrane Library were searched from inception until June 2019 to identify relevant articles. Nine long-term randomized controlled trials comparing once-weekly semaglutide or liraglutide with placebo or other active comparisons were identified. The outcomes of interest were changes in HbA1c and weight after 52 weeks. A Bayesian framework and NMA were used for data synthesis. This is a sub-study of the protocol registered in PROSPERO (number CRD42018091598). Results: The data showed significant superiority in HbA1c reduction of semaglutide 1 mg QW over liraglutide 1.2 and 1.8 mg with a treatment difference of 0.47% and 0.3%, respectively. Semaglutide 0.5 mg QW was found to be significantly superior to liraglutide 1.2 mg in HbA1c reduction with a treatment difference of 0.17%. Regarding weight reduction analysis, semaglutide 0.5 and 1 mg QW were significantly associated with a greater reduction than liraglutide 0.6 mg with a treatment difference of 2.42 and 3.06 kg, respectively. However, no significant reduction was found in comparison to liraglutide 1.2 and 1.8 mg. Conclusions: Semaglutide improved the control of blood glucose and body weight. The capacity of long-term glycemic control and body weight control of semaglutide appears to be more effective than other GLP-1 RAs, including liraglutide. However, considering the number of included studies and potential limitations, more large-scale, head-to-head, well-designed randomized-controlled trials (RCTs) are needed to confirm these findings.

POS0683 NOVEL STRINGENT OUTCOME MEASURES APPLIED TO THE PHASE 2 AND 3 ANIFROLUMAB TRIALS

Background:Patients with systemic lupus erythematosus (SLE) who received anifrolumab, a type I interferon receptor antibody, had greater BILAG–based Composite Lupus Assessment (BICLA) response rates vs placebo at Week (W)52 in the phase 2 MUSE1 and the phase 3 TULIP-12 and TULIP-23 trials. Patients receiving anifrolumab also had fewer flares, and more patients were able to taper glucocorticoids (GC) vs placebo.1–3Objectives:To evaluate anifrolumab treatment response vs placebo in patients with SLE from MUSE, TULIP-1, and TULIP-2 using more stringent BICLA definitions, as well as a novel endpoint that requires dual BICLA and SLE Responder Index (SRI[4]) responses.Methods:MUSE (NCT01438489), TULIP-1 (NCT02446912), and TULIP-2 (NCT02446899) were randomized, placebo-controlled, 52-week trials of intravenous anifrolumab (every 4 weeks for 48 weeks) in patients with moderate to severe SLE despite standard therapy.1–3 Sustained GC taper was defined as taper to ≤7.5 mg/day in patients receiving GC ≥10 mg/day at baseline, or to less than or equal to baseline dose in patients receiving GC <10 mg/day at baseline, achieved by W40 and sustained through W52. Response rates were compared between anifrolumab 300 mg vs placebo groups for patients who 1) attained a W52 BICLA response with sustained GC taper; 2) attained a W52 BICLA response and no flares after W12 (flare defined as ≥1 new BILAG-2004 A or ≥2 new BILAG-2004 B scores vs the prior visit); 3) attained a W52 BICLA response with sustained GC taper and no flares after W12; 4) attained an enhanced BICLA (eBICLA) response at W52 that required complete resolution of all baseline BILAG-2004 activity (all baseline A/B scores to D; no worsening of C or D scores); and 5) met both BICLA and SRI(4) response criteria.Results:Evaluated patients received anifrolumab 300 mg (MUSE, n=99; TULIP-1 and TULIP-2, n=180) or placebo (MUSE, n=102; TULIP-1, n=184; TULIP-2, n=182). Response rate differences favoring anifrolumab 300 mg over placebo were observed for all 5 endpoints across MUSE, TULIP-1, and TULIP-2 (Figure 1). A greater proportion of patients had BICLA responses at W52 with sustained GC taper with anifrolumab vs placebo. More patients had BICLA responses at W52 with no flares after W12 with anifrolumab vs placebo. More patients had BICLA responses at W52 with both sustained GC taper and no flares after W12 with anifrolumab vs placebo (treatment difference, 15.3%–19.3%; nominal P≤0.006). More patients attained eBICLA responses (requiring complete resolution of baseline disease activity) at W52 with anifrolumab vs placebo (treatment difference, 11.1%–14.1%; nominal P≤0.017). In addition, more patients were dual BICLA and SRI(4) responders at W52 with anifrolumab vs placebo (treatment difference, 14.3%–28.6%; nominal P≤0.004).Conclusion:In phase 2 and 3 trials in patients with SLE, anifrolumab treatment was consistently associated with improved disease control vs placebo using stringent endpoint definitions, including BICLA response with sustained GC taper and no flares, an enhanced BICLA response requiring complete resolution of baseline disease activity, and dual BICLA and SRI(4) responses.References:[1]Furie R, et al. Arthritis Rheumatol. 2017;69:376–86.[2]Furie RA, et al. Lancet Rheumatol. 2019;1:e208–19.[3]Morand EF, et al. N Engl J Med. 2020;382:211–21.Acknowledgements:Writing assistance by Rosie Butler, PhD, of JK Associates Inc., part of Fishawack Health. This study was sponsored by AstraZeneca.Disclosure of Interests:David Isenberg Consultant of: AstraZeneca, Celgene, Merck Serono, UCB, and Servier, Ian N. Bruce Speakers bureau: AstraZeneca, GSK, and UCB, Consultant of: Eli Lilly, GSK, ILTOO, Merck Serono, and UCB, Grant/research support from: Genzyme/Sanofi, GSK, Roche, and UCB, Richard Furie Consultant of: AstraZeneca, Grant/research support from: AstraZeneca, Eric F. Morand Speakers bureau: AstraZeneca, Consultant of: AstraZeneca, Grant/research support from: AstraZeneca, Yoshiya Tanaka Speakers bureau: AbbVie, Asahi Kasei, Astellas, Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, GSK, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer, Sanofi, and YL Biologics, Grant/research support from: AbbVie, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, Takeda, and UCB, Susan Manzi Consultant of: AstraZeneca, Grant/research support from: AstraZeneca, Kenneth Kalunian Consultant of: AstraZeneca, Konstantina Psachoulia Employee of: AstraZeneca, Emmanuelle Maho Employee of: AstraZeneca, Raj Tummala Employee of: AstraZeneca

358 Daridorexant Improves Sleep in Patients with Mild/Moderate Obstructive Sleep Apnea

Introduction Daridorexant is a dual orexin receptor antagonist developed for the treatment of insomnia. The effect of the highest phase-3 dose of 50 mg daridorexant on nighttime respiratory function was evaluated in patients with mild/moderate obstructive sleep apnea (OSA). This study showed that repeated doses of daridorexant had no clinically meaningful effect on the apnea-hypopnea index (AHI) or on peripheral oxygen saturation. In the same study, the effect on objective sleep parameters was also explored by polysomnography (PSG). Methods In this randomized, double-blind, placebo-controlled, two-period, crossover study, daridorexant or placebo was administered in each period once daily for 5 consecutive nights to 28 patients. Treatment difference (daridorexant – placebo) for total sleep time (TST), latency to persistent sleep (LPS), and wake after sleep onset (WASO) was analyzed for Night 5 using linear mixed-effects modeling. In addition, sleep was further explored based on sleep duration during each hour of PSG recording, duration of the different sleep phases (rapid eye movement [REM], non-REM [including N1 to N3 sleep stages]), as well as number and mean/longest duration of awakenings. Results Of 28 patients enrolled, 25 completed the study and were included in the analysis (n=15/10 with mild/moderate OSA; mean [standard deviation] AHI: 16.3 [8.2] events/h). One patient had mild insomnia symptoms at baseline. Compared to placebo, daridorexant prolonged mean TST by 38.8 min (90% confidence interval: 19.7–57.9), shortened mean LPS by 17.2 min (-35.5–1.02), and reduced mean WASO by 31.0 min (-47.3 to 14.7). Sleep architecture was maintained as no treatment differences in the duration of the evaluated sleep stages were observed when normalized to TST. Sleep duration was prolonged in the second part of the night. mean and longest duration of awakenings were decreased by a mean (90% CI) of 2.0 min (-3.1 to 0.9) and 16.3 min (-24.1 to -8.6), respectively, without treatment difference for the total number of awakenings. Conclusion Daridorexant improved objective sleep parameters in patients with mild to moderate OSA without modifying sleep architecture. Support (if any) Funded by Idorsia Pharmaceuticals Ltd.

357 Daridorexant Does Not Impair Respiratory Function in Patients with Mild/Moderate Obstructive Sleep Apnea Irrespective of Severity

Introduction Daridorexant is a dual orexin receptor antagonist developed for the treatment of insomnia. The effect of the highest phase-3 dose of 50 mg daridorexant on nighttime respiratory function was evaluated in patients with mild/moderate obstructive sleep apnea (OSA). This study showed that repeated doses of daridorexant had no clinically meaningful effect on nighttime respiration (i.e., apnea-hypopnea index [AHI] and peripheral oxygen saturation [SpO2]). In the same study, other relevant respiratory endpoints were evaluated. Methods In this randomized, double-blind, placebo-controlled, two-period, crossover study, daridorexant or placebo was administered in each period once daily for 5 consecutive nights to 28 patients. Treatment differences (daridorexant – placebo) for total number and mean/longest duration of apneas and hypopneas as well as mean and lowest SpO2 during apnea/hypopnea events in Night 5 were explored using linear mixed-effects modeling. Treatment differences for the above-mentioned endpoints versus AHI during TST at baseline (i.e., OSA severity) was analyzed by linear regression using least square approach. Results Of 28 patients enrolled, 25 completed the study and were included in the analysis (n=15/10 with mild/moderate OSA; mean [standard deviation, SD] AHI: 16.3 events/h [8.2]). Compared to placebo, daridorexant increased mean duration of TST and accordingly to a not statistically significant extent the mean number of apneas + hypopneas by 16.4 events (n=103 versus 86.2; 90% confidence interval [CI]: -0.4–33.2]) without difference in mean [SD] AHI between daridorexant (15.1 events/h [7.9] and placebo (14.2 [7.7]). No treatment difference was detected for mean (0.0 sec [-2.6–2.7]) or longest (0.8 sec [-8.9–10.5]) duration of apneas nor for mean (0.2 sec [-2.2–2.5]) or longest (8.3 sec [6.4–23.1]) duration of hypopneas. No treatment difference was observed for mean (0.3% [-0.2–2.1]) and lowest (0.9% [0.3–2.1]) SpO2 during apnea/hypopnea events. Treatment differences for any of the evaluated endpoints did not significantly correlate with AHI at baseline as a marker of OSA severity (r2 ≤ 0.09). Conclusion Daridorexant can safely be administered to patients with mild/moderate OSA as treatment differences for respiratory-related endpoints were not of statistical significance and independent of disease severity in the studied population. Support (if any) Funded by Idorsia Pharmaceuticals Ltd.

FC 071ENHANCED DEGRADATION OF 3-HYDROXY-3-METHYLGLUTARYL COENZYME A REDUCTASE (HMGCR) MAY CONTRIBUTE TO THE LOWERING OF LDL CHOLESTEROL SEEN WITH ROXADUSTAT IN CHRONIC KIDNEY DISEASE PATIENTS WITH ANEMIA

Background and Aims Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor approved in China and Japan for the treatment of anemia in patients with chronic kidney disease (CKD). In Phase 3 clinical studies, roxadustat was shown to increase hemoglobin levels in both dialysis-dependent (DD) and non-dialysis-dependent (NDD) CKD patients with anemia. This increase in hemoglobin and the accompanying decrease in hepcidin, a hormone that sequesters iron in intracellular stores, is consistent with the known role that HIF plays in the regulation of erythropoiesis. The HIF pathway may also influence cholesterol metabolism; at high altitude, total and low-density lipoprotein cholesterol (LDL-C) decrease in healthy individuals. The cholesterol biosynthesis pathway is well characterized and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) has long been recognized as the rate-limiting enzyme. Multiple feedback mechanisms are known to regulate HMGCR activity, one of which involves degradation of HMGCR via interaction with insulin-induced genes 1 and 2 (INSIG1 and INSIG2), two closely related endoplasmic reticulum membrane proteins. Here, we report clinical trial data showing a reduction in LDL-C in patients with anemia of CKD who were treated with roxadustat, and describe the results of investigation into the mechanism of this cholesterol-lowering effect. Method We studied the effect of roxadustat on LDL-C levels in human subjects and examined the potential underlying mechanisms via cell culture experiments. Clinical data were pooled from six pivotal phase 3 studies, three in patients with NDD-CKD and three in patients with DD-CKD, including those with incident dialysis (ID; on dialysis &lt;4 months at randomization). Mean changes from baseline (CFB) in LDL-C (regardless of statin use) averaged over weeks 12–28 were analyzed using a mixed ANCOVA model of repeated measures. We investigated the effect of roxadustat on HMGCR activity in a cell-free enzyme assay and on HMGCR protein levels in cultured Hep3B cells. We explored involvement of the HIF pathway in regulation of HMGCR protein levels in Hep3B cells by means of HIF-1α/HIF-2α small interfering (si)RNA knockdown. Protein expression levels were assessed by SDS-PAGE and Western blot analysis or electrochemiluminescent immunoassays. Gene expression levels were evaluated by real-time quantitative reverse-transcriptase polymerase chain reaction (RT-PCR). Results In patients with NDD-CKD, there was a 17.2% reduction in LDL-C averaged over weeks 12–28 in the roxadustat group (n=1994) vs. a 1.4% increase in the placebo group (n=1430) (least-squares mean [LSM] [SE] treatment difference = -19.83 mg/dL [1.186], p&lt;0.0001) (Table). In patients with DD-CKD, LDL-C was reduced by 18.5% in the roxadustat group (n=1650) vs. 1.7% in the epoetin alfa group (n=1741) (LSM treatment difference = -15.80 mg/dL, p&lt;0.0001) (Table). In the ID-DD patients, LDL-C dropped by 21.5% in the roxadustat group (n=680) vs. 4.6% in the epoetin alfa group (n=691) (LSM treatment difference = -17.50 mg/dL, p&lt;0.0001) (Table). After confirming that roxadustat does not directly inhibit HMGCR enzyme activity, we found that the increase in HMGCR protein levels caused by cholesterol depletion in cells was suppressed by roxadustat. However, roxadustat had no effect on HMGCR mRNA expression, indicating that the suppression of HMGCR protein levels by roxadustat was the result of an effect on protein turnover. Subsequent siRNA studies revealed that the regulation of HMGCR protein levels by roxadustat was HIF dependent and mediated via upregulation of INSIG2. Conclusion These data show that treatment with roxadustat vs. placebo or epoetin alfa lowered LDL-C in patients with NDD-CKD and DD-CKD, respectively, and highlight a potential HIF-dependent mechanism for this cholesterol-lowering effect.

A 12-month randomized controlled trial evaluating erythritol air-polishing versus curette/ultrasonic debridement of mandibular furcations in supportive periodontal therapy

Background Due to complex morphology and limited access, the cleaning of the furcation area is extremely challenging. Therefore, novel therapeutic approaches need to be tested to potentially overcome debridement limitations. The aim of the present prospective 12-month study was to compare clinical and microbiological effects following erythritol air-polishing versus conventional mechanical debridement of furcation defects in a cohort of periodontal maintenance patients. Methods Twenty patients with grade II mandibular molar furcation defects volunteered to enroll in this single-centre, examiner masked, randomized controlled trial. In a split-mouth study design, two furcation sites in each patient were randomly assigned to either receive subgingival debridement using erythritol air-polishing (test) or conventional ultrasonic/curette debridement (control) at baseline, and at 3, 6, 9 and 12 months. Probing depth, clinical attachment level and bleeding on probing were recorded at 3-month intervals. Subgingival microbiological samples obtained at baseline, 6 and 12 months were analyzed using checkerboard DNA–DNA hybridization. Discomfort from treatment was scored at 12 months using a visual analogue scale. The differences between treatments, and time-points, were tested using multilevel analysis (mixed effect models and robust variance estimates). Results A significant reduction in probing depth took place following both treatments (p < 0.001). Control sites experienced a significant mean gain in clinical attachment level of 0.5 mm (± 0.2) (p = 0.004), whereas a non-significant gain of 0.4 mm (± 0.3) was observed at test sites (p = 0.119). At 6 months, a significant between-treatment difference of 0.8 mm (± 0.4) was observed in favor of the control (p = 0.032). No significant between-treatment differences were observed in microbial load or composition. Notably, at 12 months patients experienced significantly less discomfort following air-polishing compared with control (p = 0.001). Conclusions The 12-month observations indicate that erythritol air-polishing and conventional mechanical debridement both support clinical improvements. A significant between-treatment difference in clinical attachment level was, however, detected in favour of control debridement at 6 months. In terms of patient comfort, erythritol air-polishing is superior. Trial Registration: The clinical trial was retrospectively registered in ClinicalTrial.gov with registration NCT04493398 (07/28/2020).

Treating depression with a smartphone-delivered self-help cognitive behavioral therapy for insomnia: A parallel-group randomized controlled trial

Background: Despite its efficacy in treating comorbid insomnia and depression, cognitive behavioral therapy for insomnia (CBT-I) is limited in its accessibility and, in many regions, cultural compatibility. Smartphone-based treatments is a low-cost, convenient alternative modality. This study evaluated a self-help smartphone-based CBT-I in alleviating major depression and insomnia.Methods: A parallel-group randomized, waitlist-controlled trial was conducted with 322 adults with major depression and insomnia. Participants were randomized to receive either a 6-week CBT-I via a smartphone application, proACT-S, or waitlist condition. The primary outcomes included depression severity, insomnia severity, and sleep quality. The secondary outcomes included anxiety severity, subjective health, and acceptability of treatment. Assessments were administered at baseline, post-intervention follow up (Week 6), and Week 12 follow-up. The waitlist group received treatment after the first follow-up.Results: Intention to treat analysis was conducted with multilevel modeling. In all but one models, the interaction between treatment condition and the time point at Week 6 follow-up was significant. Compared with the waitlist group, the treatment group had lower levels of depression (CES-D: treatment difference = 0.83, 95% CI [0.58, 1.09]), insomnia (ISI: treatment difference = 0.89, 95% CI [0.64, 1.16]), and anxiety (HADS-A: treatment difference = 0.80, 95% CI [0.55, 1.06]). They also had better sleep quality (PSQI: treatment difference = 0.84, 95% CI [0.58, 1.10]). No differences across any measures were found at Week 12, after the waitlist control group received the treatment. Conclusion: proACT-S is an efficacious sleep-focused self-help treatment for major depression and insomnia.

Effective treatment of Lymphogranuloma venereum proctitis with Azithromycin

Background Lymphogranuloma venereum (LGV) is a sexually transmitted infection caused by Chlamydia trachomatis (CT) serovars L1, L2, and L3 and is endemic among men who have sex with men (MSM) in Europe. We evaluated weekly oral Azithromycin 1 g for 3 weeks as a treatment for LGV proctitis. Methods This is an open clinical trial with convenience allocation according to treating physician preferences. Adults with clinical proctitis received a single dose of 1 g of intramuscular ceftriaxone and were subsequently allocated to receive (i) Doxycycline 100 mg twice daily for 21 days (Doxycycline-group) or, (ii) Azithromycin 1 g orally once weekly for 3 weeks (Azithromycin-group). LGV-cure, (primary endpoint) was defined as resolution of symptoms at week 6 (clinical cure, LGV-CC), with an additional supporting negative rectal PCR at week 4 (microbiological cure; LGV-MC), if available. Findings One hundred and twenty-five individuals with LGV clinical proctitis were included. All were MSM and 96% were HIV-positive. Eighty-two were in the Azithromycin-group and 43 in the Doxycycline-group. LGV-cure on a modified intention-to-treat analysis (primary endpoint), occurred in 80 of 82 (98%) in the Azithromycin-group versus 41 of 43 (95%) in Doxycycline-group [treatment difference (95% CI) 2.2% (-3.2; 13.2)]. LGV-MC occurred in 70 of 72 (97%) vs 15 of 15 (100%) in Azithromycin-group and Doxycycline-group, respectively [treatment difference (95% CI) -2.8% (-9.6; 17.7)]. Adverse events were similar in both treatment groups. Interpretation Our findings support extended azithromycin dosing as an alternative treatment option for symptomatic LGV proctitis and provides the rationale for future randomized trials.