Search

The late-onset GM2 gangliosidoses, comprising late-onset Tay-Sachs and Sandhoff diseases, are rare, slowly progressive, neurogenetic disorders primarily characterized by neurogenic weakness, ataxia, and dysarthria. The aim of this longitudinal study was to characterize the natural history of late-onset GM2 gangliosidoses using a number of clinical outcome assessments to measure different aspects of disease burden and progression over time, including neurological, functional, and quality of life, to inform the design of future clinical interventional trials. Patients attending the United States National Tay-Sachs & Allied Diseases Family Conference between 2015 and 2019 underwent annual clinical outcome assessments. Currently, there are no clinical outcome assessments validated to assess late-onset GM2 gangliosidoses; therefore, instruments used or designed for diseases with similar features, or to address various aspects of the clinical presentations, were used. Clinical outcome assessments included the Friedreich's Ataxia Rating Scale, the 9-Hole Peg Test, and the Assessment of Intelligibility of Dysarthric Speech. Twenty-three patients participated in at least one meeting visit (late-onset Tay-Sachs, n = 19; late-onset Sandhoff, n = 4). Patients had high disease burden at baseline, and scores for the different clinical outcome assessments were generally lower than would be expected for the general population. Longitudinal analyses showed slow, but statistically significant, neurological progression as evidenced by worsening scores on the 9-Hole Peg Test (2.68%/year, 95% CI: 0.13-5.29; p = 0.04) and the Friedreich's Ataxia Rating Scale neurological examination (1.31 points/year, 95% CI: 0.26-2.35; p = 0.02). Time since diagnosis to study entry correlated with worsening scores on the 9-Hole Peg Test (r = 0.728; p < 0.001), Friedreich's Ataxia Rating Scale neurological examination (r = 0.727; p < 0.001), and Assessment of Intelligibility of Dysarthric Speech intelligibility (r = -0.654; p = 0.001). In summary, patients with late-onset GM2 gangliosidoses had high disease burden and slow disease progression. Several clinical outcome assessments suitable for clinical trials showed only small changes and standardized effect sizes (change/standard deviation of change) over 4 years. These longitudinal natural history study results illustrate the challenge of identifying responsive endpoints for clinical trials in rare, slowly progressive, neurogenerative disorders where arguably the treatment goal is to halt or decrease the rate of decline rather than improve clinical status. Furthermore, powering such a study would require a large sample size and/or a long study duration, neither of which is an attractive option for an ultra-rare disease with no available treatment. These findings support the development of potentially more sensitive late-onset GM2 gangliosidoses-specific rating instruments and/or surrogate endpoints for use in future clinical trials., Competing Interests: Declaration of competing interest JK, CR, PM, and AH are employees of Sanofi and may hold shares and/or stock options in the company. GFC was a former employee of Sanofi through 2016, and since 2019, is the owner of Gerald Cox Rare Care Consulting, LLC and a member of the NTSAD Board of Directors. CDS and FE are neurologists volunteering at the NTSAD. CDS has provided scientific advisory for SwanBio Therapeutics and his institution has received research funding from Sanofi for a study of video oculography in late-onset GM2 gangliosidoses. CDS has received financial support from SwanBio Therapeutics, Encora Therapeutics, Sanofi, Biogen and Biohaven for the conduct of clinical trials. CDS has received honoraria from the International Parkinson's and Movement Disorders Society, the American Academy of Neurology/Continuum and Oakstone CME for the production of educational material. CDS has received grant support from the National Institutes of HealthK23 NS118045-03. FE is co-principal investigator of a gene therapy trial in GM2 sponsored by Sio Pharmaceuticals and site principal investigator of a trial on late onset GM2 sponsored by Sanofi. HL was a former employee of NYU Langone Hospital in New York City, and currently is employed by Ultragenyx and volunteers at NTSAD. JMJ and CT are employees of the Intramural Research Program (IRP) of the National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, Maryland. RK is an employee of IQVIA, which received funding from Sanofi to conduct qualitative research to develop the GM2 gangliosidoses conceptual framework, and to support selection of the COA instruments used in this study. GFC, FE, CDS, HL and CT assessed the patients and did not receive funding for their participation., (Copyright © 2024. Published by Elsevier Inc.)

Background: Variants in the GBA1 gene, which encodes lysosomal acid glucocerebrosidase, are among the most common genetic risk factors for Parkinson's disease and are associated with faster disease progression. The mechanisms involved are unresolved but might include accumulation of glucosylceramide. Venglustat is a brain-penetrant glucosylceramide synthase inhibitor that, in previous studies, reduced amounts of the glycosphingolipid. We aimed to assess the safety, efficacy, and target engagement of venglustat in people with early-stage Parkinson's disease carrying pathogenic GBA1 variants., Methods: MOVES-PD part 2 was a randomised, double-blinded, placebo-controlled phase 2 study done at 52 centres (academic sites, specialty clinics, and general neurology centres) in 16 countries. Eligible adults aged 18-80 years with Parkinson's disease (Hoehn and Yahr stage ≤2) and one or more GBA1 variants were randomly assigned using an interactive voice-response system (1:1) to 52 weeks of treatment with oral venglustat (15 mg/day) or matching placebo. Investigators, site personnel, participants, and their caregivers were masked to treatment allocation. The primary outcome measure was the change from baseline to 52 weeks in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II and III combined score (a higher score indicates greater impairment), and it was analysed in a modified intention-to-treat population (ie, all randomly assigned participants with a baseline and at least one post-baseline measurement during the treatment period). This study was registered with ClinicalTrials.gov (NCT02906020) and is closed to recruitment., Findings: Between Dec 15, 2016, and May 27, 2021, 221 participants were randomly assigned to venglustat (n=110) or placebo (n=111). The least squares mean change in MDS-UPDRS parts II and III combined score was 7·29 (SE 1·36) for venglustat (n=96) and 4·71 (SE 1·27) for placebo (n=105); the absolute difference between groups was 2·58 (95% CI -1·10 to 6·27; p=0·17). The most common treatment-emergent adverse events (TEAEs) were constipation and nausea (both were reported by 23 [21%] of 110 participants in the venglustat group and eight [7%] of 111 participants in the placebo group). Serious TEAEs were reported for 12 (11%) participants in each group. There was one death in the venglustat group owing to an unrelated cardiopulmonary arrest and there were no deaths in the placebo group., Interpretation: In people with GBA1-associated Parkinson's disease in our study, venglustat had a satisfactory safety profile but showed no beneficial treatment effect compared with placebo. These findings indicate that glucosylceramide synthase inhibition with venglustat might not be a viable therapeutic approach for GBA1-associated Parkinson's disease., Funding: Sanofi., Competing Interests: Declaration of interests AHVS declares research support from the UK Medical Research Council, Michael J Fox Foundation (MJFF), Aligning Science Across Parkinson's, and Cure Parkinson's; consulting fees from AvroBio, Auxilius, Coave, Destin, Enterin, Escape Bio, Genilac, and Sanofi; and speaking fees from the Prada Foundation. CRS declares research support from American Parkinson's Disease Foundation, MJFF, US National Institutes of Health (NIH), and US Department of Defense; consulting fees from Sanofi; a patent pending for sphingolipid biomarkers with Brigham and Women's Hospital and Sanofi; scientific advisory board participation for American Parkinson's Disease Foundation; other financial interests from Lysosomal Therapies, MJFF, NIH, Opko, Pfizer, Proteome Sciences, Sanofi, and US Department of Defense; and non-financial interests from Google. GC is an employee of Pythagoras; and declares compensation for consulting and advisory board participation from Alexion, Antisense Therapeutics, Biodelivery Sciences International, Biogen, Clinical Trial Solutions, Genentech, GW Pharmaceuticals, Immunic, Klein Buendel, MedImmune–Viela Bio, MedDay, Merck Serono, NeuroGenesis, Osmotica Pharmaceuticals, Perception Neurosciences, Reckover Pharmaceuticals, Recursion-CereXis Pharmaceuticals, Regeneron, Roche, SAb Biotherapeutics, Sanofi, and TG Therapeutics; data safety monitoring board participation for AI Therapeutics, AMO Pharmaceuticals, Applied Therapeutics, AstraZeneca, AveXis Pharmaceuticals, BioLineRx, BrainStorm Cell Therapeutics, Bristol Myers Squibb-Celgene, CSL Behring, Galmed Pharmaceuticals, Green Valley Pharma, Mapi Pharma, Merck–Pfizer, Mitsubishi Tanabe Pharma, Neurim, Novartis, Ophazyme, Opko Biologics, Reata Pharmaceuticals, Sanofi, Teva Pharmaceuticals, and VielaBio; and protocol review committee participation for the US National Heart, Lung, and Blood Institute. GUH declares compensation for consulting and advisory board participation from AbbVie, Alzprotect, Asceneuron, Biogen, Biohaven, Lundbeck, Novartis, Retrotope, Roche, Sanofi, UCB, and Weston Brain Institute; speaker honoraria from AbbVie, Biogen, Roche, Teva, UCB, and Zambon; data safety monitoring or advisory board participation for Alzprotect and Kainos Medicine; and is a patent holder for treatment of synucleinopathies (US patent number US 10,918,628 B2: EP 17 787 904.6–1109). KM declares consulting fees from Calico, Coave Therapeutics, Invicro, Lundbeck, Lysosomal Therapeutics, MJFF, NeuroDerm, Neuron23, OrbiMed, Roche, Takeda, and UBC. MJP, PM, and SPS are employees of Sanofi and might hold shares, stock options, or both, in the company. NG declares research support from Biogen, EU, Ionis, Israel Science Foundation, MJFF, and US National Parkinson Foundation; consulting fees from AbbVie, Biogen, BOL, Denali Therapeutics, NeuroDerm, Sanofi, and Sionara; speaker honoraria from AbbVie, Movement Disorders Society, and Sanofi; advisory board participation for Biogen, Denali Therapeutics, NeuroDerm, Sanofi, and Sionara; and stock ownership for BOL Pharma, GaitBetter, Lysosomal Therapeutics, and Vibrant. RNA declares research support from NIH, MJFF, Parkinson's Foundation, and US Department of Defense; and consulting fees from AVROBIO, Caraway, Gain Therapeutics, GlaxoSmithKline, Janssen, Merck, Ono Therapeutics, Sanofi, and Takeda. TGa declares research support from the EU, German Research Foundation, German Federal Ministry of Education and Research, Helmholtz Association, and MJFF; speaker honoraria from Bayer, BlueRock Therapeutics, and Coave Therapeutics; compensation for consulting and advisory board participation for MedUpdate, Novartis, Teva, and UCB; and advisory board participation for the EU. TGu declares grants from International Movement Disorders Society; consulting fees from AbbVie, NeuroDerm, Medison, Teva, and TrueMed; honoraria from AbbVie, Medison, and Teva; travel support from AbbVie, Boston Scientific, Medison, and Medtronic; unpaid advisory role or membership for Ezra Le’Marpeh Parkinson's rehabilitation programme, Israeli Huntington Disease Association, Israeli Movement Disorders Society, and Tikvah for Parkinson; stock options for Cytora; previous medical writing assistance from AbbVie and Teva; and planned patents for automated speech analysis and vocal Parkinson's disease biomarkers. TS declares research support from Biogen, MJFF, NeuroDerm, US National Institute of Neurological Disorders and Stroke, Parkinson's Foundation, and Roche; and consulting fees from Acadia, Anavex, Allergan, NeroDerm, MJFF, PhotoPharmics, Revance, Sanofi, Sunovion, Voyager, and US WorldMeds. CP declares no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Rationale & Objective: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of multiple kidney cysts that leads to growth in total kidney volume (TKV) and progression to kidney failure. Venglustat is a glucosylceramide synthase inhibitor that has been shown to inhibit cyst growth and reduce kidney failure in preclinical models of ADPKD., Study Design: STAGED-PKD was a 2-stage, multicenter, double-blind, randomized, placebo-controlled phase 2/3 study in adults with ADPKD at risk of rapidly progressive disease, who were selected based on Mayo Clinic imaging classification of ADPKD class 1C, 1D, or 1E and an estimated glomerular filtration rate (eGFR) of 30-89.9mL/min/1.73m 2 ., Setting & Participants: Enrollment included 236 and 242 patients in stages 1 and 2, respectively., Interventions: In trial stage 1, the patients were randomized 1:1:1 to venglustat, 8mg; venglustat, 15mg; or placebo. In stage 2, the patients were randomized 1:1 to venglustat, 15mg (highest dose identified as safe and well tolerated in stage 1), or placebo., Outcomes: Primary end points were rate of change in TKV over 18 months in stage 1 and eGFR slope over 24 months in stage 2. Secondary end points were eGFR slope over 18 months (stage 1), rate of change in TKV (stage 2), and safety/tolerability, pain, and fatigue (stages 1 and 2)., Results: A prespecified interim futility analysis showed that venglustat treatment had no effect on the annualized rate of change in TKV over 18 months (stage 1) and had a faster rate of decline in eGFR slope over 24 months (stage 2). Due to this lack of efficacy, the study was terminated early., Limitations: The short follow-up period after the end of treatment and limited generalizability of the findings., Conclusions: In patients with rapidly progressing ADPKD, treatment with venglustat at either 8mg or 15mg showed no change in the rate of change in TKV and a faster rate of eGFR decline in STAGED-PKD despite a dose-dependent decrease in plasma glucosylceramide levels., Funding: This study was funded by Sanofi., Trial Registration: Registered at ClinicalTrials.gov with study number NCT03523728., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Gaucher disease type 3 is a chronic neuronopathic disorder with wide-ranging effects, including hepatosplenomegaly, anaemia, thrombocytopenia, skeletal disease and diverse neurological manifestations. Biallelic mutations in GBA1 reduce lysosomal acid β-glucosidase activity, and its substrates, glucosylceramide and glucosylsphingosine, accumulate. Enzyme replacement therapy and substrate reduction therapy ameliorate systemic features of Gaucher disease, but no therapies are approved for neurological manifestations. Venglustat is an investigational, brain-penetrant, glucosylceramide synthase inhibitor with potential to improve the disease by rebalancing influx of glucosylceramide with impaired lysosomal recycling. The Phase 2, open-label LEAP trial (NCT02843035) evaluated orally administered venglustat 15 mg once-daily in combination with maintenance dose of imiglucerase enzyme replacement therapy during 1 year of treatment in 11 adults with Gaucher disease type 3. Primary endpoints were venglustat safety and tolerability and change in concentration of glucosylceramide and glucosylsphingosine in CSF from baseline to Weeks 26 and 52. Secondary endpoints included change in plasma concentrations of glucosylceramide and glucosylsphingosine, venglustat pharmacokinetics in plasma and CSF, neurologic function, infiltrative lung disease and systemic disease parameters. Exploratory endpoints included changes in brain volume assessed with volumetric MRI using tensor-based morphometry, and resting functional MRI analysis of regional brain activity and connectivity between resting state networks. Mean (SD) plasma venglustat AUC0-24 on Day 1 was 851 (282) ng•h/ml; Cmax of 58.1 (26.4) ng/ml was achieved at a median tmax 2.00 h. After once-daily venglustat, plasma concentrations (4 h post-dose) were higher compared with Day 1, indicating ∼2-fold accumulation. One participant (Patient 9) had low-to-undetectable venglustat exposure at Weeks 26 and 52. Based on mean plasma and CSF venglustat concentrations (excluding Patient 9), steady state appeared to be reached on or before Week 4. Mean (SD) venglustat concentration at Week 52 was 114 (65.8) ng/ml in plasma and 6.14 (3.44) ng/ml in CSF. After 1 year of treatment, median (inter-quartile range) glucosylceramide decreased 78% (72, 84) in plasma and 81% (77, 83) in CSF; median (inter-quartile range) glucosylsphingosine decreased 56% (41, 60) in plasma and 70% (46, 76) in CSF. Ataxia improved slightly in nine patients: mean (SD, range) total modified Scale for Assessment and Rating of Ataxia score decreased from 2.68 [1.54 (0.0 to 5.5)] at baseline to 1.55 [1.88 (0.0 to 5.0)] at Week 52 [mean change: -1.14 (95% CI: -2.06 to -0.21)]. Whole brain volume increased slightly in patients with venglustat exposure and biomarker reduction in CSF (306.7 ± 4253.3 mm3) and declined markedly in Patient 9 (-13894.8 mm3). Functional MRI indicated stronger connectivity at Weeks 26 and 52 relative to baseline between a broadly distributed set of brain regions in patients with venglustat exposure and biomarker reduction but not Patient 9, although neurocognition, assessed by Vineland II, deteriorated in all domains over time, which illustrates disease progression despite the intervention. There were no deaths, serious adverse events or discontinuations. In adults with Gaucher disease type 3 receiving imiglucerase, addition of once-daily venglustat showed acceptable safety and tolerability and preliminary evidence of clinical stability with intriguing but intrinsically inconsistent signals in selected biomarkers, which need to be validated and confirmed in future research., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Rationale & Objective: Venglustat, a glucosylceramide synthase inhibitor, inhibits cyst growth and reduces kidney failure in mouse models of autosomal dominant polycystic kidney disease (ADPKD). STAGED-PKD aims to determine the safety and efficacy of venglustat and was designed using patient enrichment for progression to end-stage kidney disease and modeling from prior ADPKD trials., Study Design: STAGED-PKD is a 2-stage, international, double-blind, randomized, placebo-controlled trial in adults with ADPKD (Mayo Class 1C-1E) and estimated glomerular filtration rate (eGFR) 45-<90 mL/min/1.73 m 2 at risk of rapidly progressive disease. Enrichment for rapidly progressing patients was identified based on retrospective analysis of total kidney volume (TKV) and eGFR slope from the combined Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease and HALT Progression of Polycystic Kidney Disease A studies., Setting & Participants: Target enrollment in stages 1 and 2 was 240 and 320 patients, respectively., Interventions: Stage 1 randomizes patients 1:1:1 to venglustat 8 mg or 15 mg once daily or placebo. Stage 2 randomizes patients 1:1 to placebo or venglustat, with the preferred dose based on stage 1 safety data., Outcomes: Primary endpoints are TKV growth rate over 18 months in stage 1 and eGFR slope over 24 months in stage 2. Secondary endpoints include: annualized rate of change in eGFR from baseline to 18 months (stage 1); annualized rate of change in TKV based on magnetic resonance imaging from baseline to 18 months (stage 2); and safety, tolerability, pain, and fatigue (stages 1 and 2)., Limitations: If stage 1 is unsuccessful, patients enrolled in the trial may develop drug-related adverse events that can have long-lasting effects., Conclusions: Modeling allows the design and powering of a 2-stage combined study to assess venglustat's impact on TKV growth and eGFR slope. Stage 1 TKV assessment via a nested approach allows early evaluation of efficacy and increased efficiency of the trial design by reducing patient numbers and trial duration., Funding: This study was funded by Sanofi., Trial Registration: STAGED-PKD has been registered at ClinicalTrials.gov with study number NCT03523728., (© 2022 The Authors.)

Background: Glucocerebrosidase gene (GBA) mutations influence risk and prognosis of Parkinson's disease (PD), possibly through accumulation of glycosphingolipids, including glucosylceramide (GL-1). Venglustat is a novel, brain penetrant glucosylceramide synthase inhibitor., Objective: Evaluate venglustat pharmacology, safety, and tolerability in patients with PD and GBA mutations (GBA-PD)., Methods: Part 1 of the phase 2 MOVES-PD trial (NCT02906020) was a randomized, double-blinded, placebo-controlled, dose-escalation study performed in six countries. Eligible participants included Japanese and non-Japanese patients aged 18-80 years with PD diagnosis and heterozygous GBA mutation. Participants were randomized to three doses of once-daily oral venglustat or placebo and were followed up to 36 weeks (Japanese participants: 52 weeks). Primary endpoint was venglustat safety and tolerability versus placebo. Secondary and exploratory endpoints included venglustat pharmacokinetics and pharmacodynamics., Results: Participants (N = 29) received venglustat (Japanese, n = 9; non-Japanese, n = 13) or placebo (n = 3; n = 4). Eight (89%) Japanese and 12 (92%) non-Japanese venglustat-treated participants experienced at least one adverse event (AE) versus two (67%) and four (100%) participants from the respective placebo groups. Most AEs were mild or moderate; no serious AEs or deaths occurred. Two venglustat-treated non-Japanese participants discontinued due to AEs (confusional state and panic attack). Over 4 weeks, venglustat exposure in plasma and cerebrospinal fluid (CSF) increased, and GL-1 levels in plasma and CSF decreased, both in a dose-dependent manner. At the highest dose, CSF GL-1 decreased by 72.0% in Japanese and 74.3% in non-Japanese participants., Conclusion: Venglustat showed favorable safety and tolerability in MOVES-PD Part 1 and target engagement was achieved in CSF.

Background and Aims: Elevated lipoprotein(a) [Lp(a)] levels are considered a causal factor for cardiovascular disease. In phase 3 ODYSSEY trials, alirocumab reduced levels of low-density lipoprotein cholesterol (LDL-C) and Lp(a), with concomitant reductions in the risk of major adverse cardiovascular events (MACE). We assessed whether lower on-study and greater percentage reductions in Lp(a) are associated with a lower risk of MACE., Methods: Post-hoc analysis of data pooled from 10 phase 3 ODYSSEY trials comparing alirocumab with control (placebo or ezetimibe) in patients (n = 4983) with cardiovascular disease and/or risk factors, and hypercholesterolemia despite statin/other lipid-lowering therapies., Results: Median (Q1, Q3) baseline Lp(a) levels were 23.5 (8.0, 67.0) mg/dL. Median Lp(a) changes from baseline with alirocumab were -25.6% vs. -2.5% with placebo (absolute reductions 6.8 vs. 0.5 mg/dL) in placebo-controlled trials, and -21.4% vs. 0.0% with ezetimibe (4.5 vs. 0.0 mg/dL) in ezetimibe-controlled trials. During follow-up (6699 patient-years), 104 patients experienced MACE. A 12% relative risk reduction in MACE per 25% reduction in Lp(a) (p=0.0254) was no longer significant after adjustment for LDL-C changes: hazard ratio per 25% reduction: 0.89 (95% confidence interval, 0.79-1.01; p=0.0780). In subgroup analysis, the association between Lp(a) reduction and MACE remained significant in a fully adjusted model among participants with baseline Lp(a) ≥50 mg/dL (p-interaction vs. Lp(a) < 50 mg/dL: 0.0549)., Conclusions: In this population, Lp(a) reductions were not significantly associated with MACE independently of LDL-C reductions. Reducing the risk of MACE by targeting Lp(a) may require greater reductions in Lp(a) with more potent therapies and/or higher initial Lp(a) levels., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: The objective of this study is to report the dose response in ODYSSEY phase 3 clinical trials of proprotein convertase subtilisin kexin type 9 inhibition with alirocumab in patients not at prespecified lipid goals who received a per-protocol dose increase from 75 every 2 weeks (Q2W) to 150 mg Q2W., Methods: Patients (n=2181) receiving statins were enrolled in six phase 3 randomized, double-blind, double-dummy trials (24-104 weeks): alirocumab versus placebo or ezetimibe 10 mg/day. The 75 mg subcutaneous Q2W dose was increased to 150 mg at week 12 if week 8 LDL cholesterol (LDL-C) was greater than or equal to 70 mg/dl (>100 mg/dl in OPTIONS studies for patients without previous coronary heart disease, but with other risk factors). LDL-C percentage reductions from baseline (on-treatment data, n=1291) were compared at week 12 versus week 24., Results: Most patients (n=951; 73.7%) with 75 mg Q2W dose plus background statin achieved LDL-C less than 70 or less than 100 mg/dl at week 8. In 340 (26.3%) patients, alirocumab dose was increased to 150 mg Q2W at week 12, and 60.9% of these patients achieved LDL-C goals at week 24, with an additional 14.2% reduction in LDL-C from week 12 to week 24. Adverse event rates were comparable in patients with versus without a dose increase (72.4 vs. 71.8% in placebo-controlled trials; 67.0 vs. 67.6% in ezetimibe-controlled trials)., Conclusion: Most patients achieved LDL-C goals with alirocumab 75 mg Q2W plus statins. Of those (26.3%) receiving a dose increase, 60.9% achieved LDL-C goals at week 24 with an additional 14.2% reduction in LDL-C.

Elevated lipoprotein(a) [Lp(a)] is independently associated with increased cardiovascular risk. However, treatment options for elevated Lp(a) are limited. Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9, reduced low-density lipoprotein cholesterol (LDL-C) by up to 62% from baseline in phase 3 studies, with adverse event rates similar between alirocumab and controls. We evaluated the effect of alirocumab on serum Lp(a) using pooled data from the phase 3 ODYSSEY program: 4,915 patients with hypercholesterolemia from 10 phase 3 studies were included. Eight studies evaluated alirocumab 75 mg every 2 weeks (Q2W), with possible increase to 150 mg Q2W at week 12 depending on LDL-C at week 8 (75/150 mg Q2W); the other 2 studies evaluated alirocumab 150-mg Q2W from the outset. Comparators were placebo or ezetimibe. Eight studies were conducted on a background of statins, and 2 studies were carried out with no statins. Alirocumab was associated with significant reductions in Lp(a), regardless of starting dose and use of concomitant statins. At week 24, reductions from baseline were 23% to 27% with alirocumab 75/150-mg Q2W and 29% with alirocumab 150-mg Q2W (all comparisons p <0.0001 vs controls). Reductions were sustained over 78 to 104 weeks. Lp(a) reductions with alirocumab were independent of race, gender, presence of familial hypercholesterolemia, baseline Lp(a), and LDL-C concentrations, or use of statins. In conclusion, in addition to marked reduction in LDL-C, alirocumab leads to a significant and sustained lowering of Lp(a)., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Patients with heterozygous familial hypercholesterolemia (HeFH) are characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels. Long-term effects of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition have not been thoroughly investigated in these patients., Objective: We evaluated efficacy and safety of alirocumab, a PCSK9 inhibitor, vs placebo in patients with HeFH., Methods: In total, 1257 patients with HeFH on maximally tolerated statin ± other lipid-lowering therapies from four 78-week ODYSSEY trials were analyzed. In FH I and II, patients with baseline LDL-C levels ≥70/100 mg/dL (n = 735), depending on documented cardiovascular disease history, received placebo or alirocumab 75 mg every 2 weeks (Q2W; with dose increase to 150 mg Q2W at week 12 if week 8 LDL-C was ≥70 mg/dL). Separately, data were pooled from HIGH FH (baseline LDL-C ≥160 mg/dL) and patients with HeFH from LONG TERM (baseline LDL-C ≥70 mg/dL), where patients received placebo or alirocumab 150 mg Q2W (n = 522)., Results: At week 24, alirocumab reduced LDL-C levels by -48.8% (75/150 mg Q2W; placebo: +7.1%) and -55.0% (alirocumab 150 mg Q2W; placebo: +1.3%) (both P < .0001 vs placebo; intention-to-treat analysis). Least-squares mean LDL-C levels of 69.1 to 75.6 mg/dL (alirocumab 75/150 mg/dL Q2W; baseline: 141.3 mg/dL) and 72.2 to 82.3 mg/dL (alirocumab 150 mg Q2W; baseline: 168.4 mg/dL) were achieved at weeks 24 to 78 (on-treatment analysis). Additional beneficial effects were observed in other lipids. Treatment-emergent adverse event rates were similar in the alirocumab (80.5%) and placebo groups (83.0%)., Conclusions: In this large cohort of patients with HeFH, alirocumab significantly reduced LDL-C levels. Alirocumab was generally well tolerated., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: A continuous relationship between reductions in low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events (MACE) has been observed in statin and ezetimibe outcomes trials down to achieved levels of 54 mg/dL. However, it is uncertain whether this relationship extends to LDL-C levels <50 mg/dL. We assessed the relationship between additional LDL-C, non-high-density lipoprotein cholesterol, and apolipoprotein B100 reductions and MACE among patients within the ODYSSEY trials that compared alirocumab with controls (placebo/ezetimibe), mainly as add-on therapy to maximally tolerated statin., Methods: Data were pooled from 10 double-blind trials (6699 patient-years of follow-up). Randomization was to alirocumab 75/150 mg every 2 weeks or control for 24 to 104 weeks, added to background statin therapy in 8 trials. This analysis included 4974 patients (3182 taking alirocumab, 1174 taking placebo, 618 taking ezetimibe). In a post hoc analysis, the relationship between average on-treatment lipid levels and percent reductions in lipids from baseline were correlated with MACE (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization) in multivariable analyses., Results: Overall, 33.1% of the pooled cohort achieved average LDL-C <50 mg/dL (44.7%-52.6% allocated to alirocumab, 6.5% allocated to ezetimibe, and 0% allocated to placebo). In total, 104 patients experienced MACE (median time to event, 36 weeks). For every 39 mg/dL lower achieved LDL-C, the risk of MACE appeared to be 24% lower (adjusted hazard ratio, 0.76; 95% confidence interval, 0.63-0.91; P=0.0025). Percent reductions in LDL-C from baseline were inversely correlated with MACE rates (hazard ratio, 0.71; 95% confidence interval, 0.57-0.89 per additional 50% reduction from baseline; P=0.003). Strengths of association materially similar to those described for LDL-C were observed with achieved non-high-density lipoprotein cholesterol and apolipoprotein B100 levels or percentage reductions., Conclusions: In a post hoc analysis from 10 ODYSSEY trials, greater percentage reductions in LDL-C and lower on-treatment LDL-C were associated with a lower incidence of MACE, including very low levels of LDL-C (<50 mg/dL). These findings require further validation in the ongoing prospective ODYSSEY OUTCOMES trial., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01507831, NCT01623115, NCT01709500, NCT01617655, NCT01644175, NCT01644188, NCT01644474, NCT01730040, NCT01730053, and NCT01709513., (© 2016 The Authors.)

Objectives: Despite maximally tolerated statin therapy, many patients with high cardiovascular risk, with or without heterozygous familial hypercholesterolemia may require additional low-density lipoprotein cholesterol (LDL-C) reduction. We report pooled alirocumab (ALI) efficacy and safety data from eight Phase 3 trials in 4629 hypercholesterolemia patients, receiving background statin therapy., Material and Methods: Studies were pooled by ALI dose and control: ALI 75/150mg every 2weeks (Q2W; dose increased to 150mg Q2W at Week 12 based on Week 8 LDL-C) versus ezetimibe (EZE; Pool 1) or placebo (PBO; Pool 2), and ALI 150mg Q2W versus PBO (Pool 3)., Results: Mean baseline LDL-C was 109 vs. 105mg/dL (Pool 1), 129 vs. 130mg/dL (Pool 2) and 126 vs. 125mg/dL (Pool 3). ALI 75/150mg Q2W reduced LDL-C by 48.9% (vs. -19.3% EZE) and 48.6% (vs. +4.2% PBO) from baseline to Week 24, and ALI 150mg Q2W reduced LDL-C by 60.4% (vs. +0.5% PBO; all p<0.0001). LDL-C reductions were sustained to Week 104. Risk-based LDL-C goals (<70mg/dL or <100mg/dL) were achieved by 78.0%, 75.2%, and 79.0% (Pool 1-3) of ALI-treated patients (vs. 52.4%, 6.4%, and 8.4%, respectively, for controls) at Week 24. Consistent reductions were observed in apolipoprotein B, non-high-density lipoprotein cholesterol, and lipoprotein (a) (p<0.0001 vs. control). Common adverse events in ALI-treated patients were nasopharyngitis, injection-site reactions, upper respiratory tract infections, and influenza., Conclusions: Alirocumab treatment significantly reduced LDL-C in high cardiovascular risk patients, enabling most to achieve risk-based LDL-C goals., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Importance: The optimal anticoagulant for patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) managed with an invasive strategy remains controversial., Objective: To compare the clinical efficacy and safety of otamixaban, a novel intravenous direct factor Xa inhibitor, with that of unfractionated heparin plus downstream eptifibatide in patients with NSTE-ACS undergoing a planned early invasive strategy., Design, Setting, and Participants: Randomized, double-blind, active-controlled superiority trial that enrolled 13,229 patients with NSTE-ACS and a planned early invasive strategy, at 568 active sites in 55 countries and conducted between April 2010 and February 2013. A planned interim analysis was conducted for otamixaban dose selection., Interventions: Eligible participants were randomized to otamixaban (bolus and infusion, at 1 of 2 doses) or unfractionated heparin plus, at the time of percutaneous coronary intervention, eptifibatide. The otamixaban dose selected at interim analysis was an intravenous bolus of 0.080 mg/kg followed by an infusion of 0.140 mg/kg per hour., Main Outcomes and Measures: The primary efficacy outcome was the composite of all-cause death or new myocardial infarction through day 7., Results: Rates of the primary efficacy outcome were 5.5% (279 of 5105 patients) randomized to receive otamixaban and 5.7% (310 of 5466 patients) randomized to receive unfractionated heparin plus eptifibatide (adjusted relative risk, 0.99 [95% CI, 0.85-1.16]; P = .93). There were no differences for the secondary end points, including procedural thrombotic complications. The primary safety outcome of Thrombosis in Myocardial Infarction major or minor bleeding through day 7 was increased by otamixaban (3.1% vs 1.5%; relative risk, 2.13 [95% CI, 1.63-2.78]; P < .001). Results were consistent across prespecified subgroups., Conclusions and Relevance: Otamixaban did not reduce the rate of ischemic events relative to unfractionated heparin plus eptifibatide but did increase bleeding. These findings do not support the use of otamixaban for patients with NSTE-ACS undergoing planned early percutaneous coronary intervention., Trial Registration: clinicaltrials.gov Identifier: NCT01076764.

Objective: This study aimed to assess the impact of combination antithrombotic therapy on stroke and bleeding risk compared with anticoagulation therapy only in patients with atrial fibrillation (AF)., Methods: Post hoc analysis of 4,576 patients with AF (mean ± SD age, 70.1 ± 9.1 years; men, 66.5%) enrolled in the Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation (AMADEUS) trial were randomized to receive either subcutaneous idraparinux (2.5 mg weekly) (n = 2,283) or dose-adjusted vitamin K antagonists (VKAs) (international normalized ratio, 2.0-3.0) (n = 2,293). Of these patients, 848 (18.5%) received antiplatelet therapy (aspirin, clopidogrel, ticlopidine, etc) in addition to anticoagulation treatment (combination antithrombotic therapy)., Results: A total of 572 (15.3% per year) clinically relevant bleeding and 103 (2.6% per year) major bleeding events occurred. Patients receiving combination antithrombotic therapy had a 2.3- to 2.5-fold increased risk of clinically relevant bleeding events and major bleeding events, respectively, compared with those receiving anticoagulation therapy only. Multivariate analyses (hazard ratio, 95% CI) revealed that the risk of clinically relevant bleeding was significantly increased by age 65 to 74 years (1.44, 1.14-1.82) and ≥ 75 years (1.59, 1.24-2.04, P = .001) and by combination antithrombotic therapy (2.47, 2.07-2.96, P < .0001). The same held true for major bleeding events, with analogous figures for age 65 to 74 years (2.26, 1.08-4.71) and ≥ 75 years (4.19, 1.98-8.87, P = .0004) and for combination antithrombotic therapy (2.23, 1.49-3.34, P < .0001). Combination antithrombotic therapy was not associated with a decrease in ischemic stroke risk compared with anticoagulation therapy only (11 [1.4% per year] vs 22 [0.7% per year]; adjusted hazard ratio, 2.01; 95% CI, 0.94-4.30; P = .07)., Conclusions: Combination antithrombotic therapy increases the risk of clinically relevant bleeding and major bleeding in patients with AF and does not appear to reduce the risk of stroke.

Background & Aims: Cirrhotic patients with recurrent ascites frequently require paracentesis despite diuretic therapy. Vasopressin receptor antagonists, by increasing free water clearance, may reduce the recurrence of ascites. To investigate the effects of the addition of a vasopressin V(2) receptor antagonist, satavaptan, to 100mg spironolactone on ascites recurrence after a large volume paracentesis in patients with liver cirrhosis irrespective of the presence of hyponatraemia., Methods: One hundred and fifty one cirrhotic patients with recurrent ascites with or without hyponatraemia, and normal to mildly abnormal renal function were randomised in a double-blind study to receive either 5mg (n=39), 12.5mg (n=36), 25mg (n=40) of satavaptan or placebo (n=36) for 12 weeks. Their Child-Pugh scores were 9.2+/-1.3, 8.7+/-1.7, 8.8+/-1.3, and 9.0+/-1.5, respectively., Results: Median time to first paracentesis was 23, 26, and 17 days with satavaptan 5, 12.5, and 25mg, respectively, versus 14 days with placebo (ns for all doses). The frequency of paracenteses was decreased significantly (p<0.05) in all satavaptan groups versus placebo. Mean increase in ascites was 2.82+/-0.48 L/week for placebo versus 2.12+/-0.40, 2.14+/-0.33, and 2.06+/-0.40 L/week for the 5, 12.5, and 25mg of satavaptan, respectively (ns for all doses). Similar numbers of patients experienced major adverse events in all groups. Increases in serum creatinine, orthostatic changes in systolic pressure and thirst were more common with satavaptan., Conclusions: Satavaptan has the potential to reduce recurrence of ascites after a large volume paracentesis at doses from 5 to 25mg in cirrhotic patients with ascites., (Copyright 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

This paper highlights the consequences of incomplete observations in the analysis of longitudinal binary data, in particular non-monotone missing data patterns. Sensitivity analysis is advocated and a method is proposed based on a log-linear model. A sensitivity parameter that represents the relationship between the response mechanism and the missing data mechanism is introduced. It is shown that although this parameter is identifiable, its estimation is highly questionable. A far better approach is to consider a range of plausible values and to estimate the parameters of interest conditionally upon each value of the sensitivity parameter. This allows us to assess the sensitivity of study's conclusion to assumptions regarding the missing data mechanism. The method is applied to a randomized clinical trial comparing the efficacy of two treatment regimens in patients with persistent asthma.

We propose to perform a sensitivity analysis to evaluate the extent to which results from a longitudinal study can be affected by informative drop-outs. The method is based on a selection model, where the parameter relating the dropout probability to the current observation is not estimated, but fixed to a set of values. This allows to evaluate several hypotheses for the degree of informativeness of the drop-out process. Expectation and variance of missing data, conditional on the drop-out time are computed, and a stochastic EM algorithm is used to obtain maximum likelihood estimates. Simulations show that when the drop-out parameter is correctly specified, unbiased estimates of the other parameters are obtained, and coverage percentages of their confidence intervals are close to their theoretical value. More interestingly, misspecification of the drop-out parameter does not considerably alter these results. This method was applied to a randomized clinical trial, designed to demonstrate non-inferiority of an inhaled corticosteroid in terms of bone density, compared with a reference treatment. Sensitivity analysis showed that the conclusion of non-inferiority was robust against different hypotheses for the drop-out process., (Copyright 2004 John Wiley & Sons, Ltd.)

Multiplicity of inferences is present in a large majority of clinical trials and conducts to false analyses or interpretation issues. The main risk consists in false positive conclusions. A large number of statistical methods is available for controlling the rate of false positive conclusions. But formal adjustment is not necessary in all cases and depends on the aims of the study.

Objective: Inhaled corticosteroids are recommended as first-line therapy for pediatric asthma. However, few controlled long-term studies have investigated their effect on bone mineral density (BMD) and growth., Methods: Children who were aged 6 to 14 years and had persistent asthma were randomized to 24 months' treatment with fluticasone propionate (FP) 200 micro g/d or nedocromil sodium (NS) 8 mg/d (if uncontrolled, maximum doses of 400 micro g/d and 16 mg/d, respectively). BMD was assessed blind and analyzed at a central facility on the basis of dual-energy x-ray absorptiometry measurements of the lumbar spine and femoral neck at months 0, 6, 12, and 24. Height was measured at months 0, 12, and 24. Efficacy parameters (lung function, asthma control, occurrence of exacerbations) were measured every 3 months., Results: In total, 174 children were randomized to treatment (87 received FP, and 87 received NS). At month 24, the adjusted mean percentage increase in lumbar spine BMD was 11.6% in the FP group compared with 10.4% in NS-treated children (95% confidence interval for treatment difference: -0.7% to 3.1%). The corresponding increases in femoral neck BMD were 8.9% and 8.5%, respectively. There was no significant difference in growth between the 2 groups: adjusted mean growth rates were 6.1 cm/y with FP and 5.8 cm/y with NS. FP was significantly superior for every efficacy parameter investigated and was similarly well tolerated as NS., Conclusions: The long-term effects of FP and NS on BMD accrual and growth are similar among children with asthma. The benefit:risk ratio of FP may be considered superior to that of NS.