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Ophthalmology Jun 2024To evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2 and vascular endothelial growth factor (VEGF) A pathway inhibition with intravitreal... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2 and vascular endothelial growth factor (VEGF) A pathway inhibition with intravitreal faricimab according to a personalized treat-and-extend (T&E)-based regimen with up to every-16-week dosing in the YOSEMITE and RHINE (ClinicalTrials.gov identifiers, NCT03622580 and NCT03622593, respectively) phase 3 trials of diabetic macular edema (DME).
DESIGN
Randomized, double-masked, noninferiority phase 3 trials.
PARTICIPANTS
Adults with visual acuity loss (best-corrected visual acuity [BCVA] of 25-73 letters) due to center-involving DME.
METHODS
Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks, faricimab 6.0 mg T&E (previously referred to as personalized treatment interval), or aflibercept 2.0 mg every 8 weeks. The T&E up to every-16-week dosing regimen was based on central subfield thickness (CST) and BCVA change.
MAIN OUTCOME MEASURES
Included changes from baseline in BCVA and CST, number of injections, durability, absence of fluid, and safety through week 100.
RESULTS
In YOSEMITE and RHINE (n = 940 and 951, respectively), noninferior year 1 visual acuity gains were maintained through year 2; mean BCVA change from baseline at 2 years (weeks 92, 96, and 100 average) with faricimab every 8 weeks (YOSEMITE and RHINE, +10.7 letters and +10.9 letters, respectively) or T&E (+10.7 letters and +10.1 letters, respectively) were comparable with aflibercept every 8 weeks (+11.4 letters and +9.4 letters, respectively). The median number of study drug injections was lower with faricimab T&E (YOSEMITE and RHINE, 10 and 11 injections, respectively) versus faricimab every 8 weeks (15 injections) and aflibercept every 8 weeks (14 injections) across both trials during the entire study. In the faricimab T&E arms, durability was improved further during year 2, with > 60% of patients receiving every-16-week dosing and approximately 80% receiving every-12-week or longer dosing at week 96. Almost 80% of patients who achieved every-16-week dosing at week 52 maintained every-16-week dosing without an interval reduction through week 96. Mean CST reductions were greater (YOSEMITE/RHINE weeks 92/96/100 average: faricimab every 8 weeks -216.0/-202.6 µm, faricimab T&E -204.5/-197.1 µm, aflibercept every 8 weeks -196.3/-185.6 µm), and more patients achieved absence of DME (CST < 325 μm; YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 87%-92%/88%-93%, faricimab T&E 78%-86%/85%-88%, aflibercept every 8 weeks 77%-81%/80%-84%) and absence of intraretinal fluid (YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 59%-63%/56%-62%, faricimab T&E 43%-48%/45%-52%, aflibercept every 8 weeks 33%-38%/39%-45%) with faricimab every 8 weeks or T&E versus aflibercept every 8 weeks through year 2. Overall, faricimab was well tolerated, with a safety profile comparable with that of aflibercept.
CONCLUSIONS
Clinically meaningful visual acuity gains from baseline, anatomic improvements, and extended durability with intravitreal faricimab up to every 16 weeks were maintained through year 2. Faricimab given as a personalized T&E-based dosing regimen supports the role of dual angiopoietin-2 and VEGF-A inhibition to promote vascular stability and to provide durable efficacy for patients with DME.
FINANCIAL DISCLOSURE(S)
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Topics: Humans; Macular Edema; Diabetic Retinopathy; Visual Acuity; Intravitreal Injections; Double-Blind Method; Male; Female; Middle Aged; Angiogenesis Inhibitors; Vascular Endothelial Growth Factor A; Aged; Tomography, Optical Coherence; Treatment Outcome; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Angiopoietin-2; Follow-Up Studies; Antibodies, Monoclonal, Humanized
PubMed: 38158159
DOI: 10.1016/j.ophtha.2023.12.026 -
The Canadian Journal of Cardiology Dec 2023Depressed low-density lipoprotein cholesterol concentration protects against atherosclerotic cardiovascular disease. Natural hypocholesterolemia states can have a... (Review)
Review
Depressed low-density lipoprotein cholesterol concentration protects against atherosclerotic cardiovascular disease. Natural hypocholesterolemia states can have a monogenic etiology, caused by pathogenic loss of function variants in the PCSK9, ANGPTL3, MTTP, or APOB genes. In this focused review, we discuss development and clinical use of several new therapeutics that inhibit these gene products to target elevated levels of low-density lipoprotein cholesterol. In particular, inhibitors of proprotein convertase subtilisin kexin type 9 (PCSK9) have notably affected clinical practice, followed recently by inhibition of angiopoietin-like 3 (ANGPTL3). Currently used in the clinic are alirocumab and evolocumab, two anti-PCSK9 monoclonal antibodies, inclisiran, a small interfering RNA that prevents PCSK9 translation, evinacumab, an anti-ANGPTL3 monoclonal antibody, and lomitapide, a small-molecule inhibitor of microsomal triglyceride transfer protein. Additional therapies are in preclinical or clinical trial stages of development. These consist of other monoclonal antibodies, antisense oligonucleotides, small-molecule inhibitors, mimetic peptides, adnectins, vaccines, and gene-editing therapies. Vaccines and gene-editing therapies in particular hold great potential to confer active long-term attenuation or provide single-treatment life-long knock-down of PCSK9 or ANGPTL3 activity. Biologic therapies inspired by monogenic hypocholesterolemia states are becoming valuable tools to help protect against atherosclerotic cardiovascular disease.
Topics: Humans; Cholesterol, LDL; Proprotein Convertase 9; PCSK9 Inhibitors; Cardiovascular Diseases; Antibodies, Monoclonal; Atherosclerosis; Biological Therapy; Vaccines; Anticholesteremic Agents; Angiopoietin-Like Protein 3
PubMed: 37562541
DOI: 10.1016/j.cjca.2023.08.003 -
Cardiovascular Research Aug 2023Angiopoietin-like protein 8 (ANGPTL8) plays important roles in lipid metabolism, glucose metabolism, inflammation, and cell proliferation and migration. Clinical studies...
AIMS
Angiopoietin-like protein 8 (ANGPTL8) plays important roles in lipid metabolism, glucose metabolism, inflammation, and cell proliferation and migration. Clinical studies have indicated that circulating ANGPTL8 concentrations are increased in patients with hypertension and positively associated with blood pressure. ANGPTL8 deficiency ameliorates blood pressure in mice treated with chronic intermittent hypoxia. Currently, little is known regarding the pathophysiological role of the vascular smooth muscle cell (VSMC)-derived ANGPTL8 in hypertension and hypertensive cardiovascular remodelling.
METHODS AND RESULTS
Circulating ANGPTL8 concentrations, as determined by enzyme-linked immunosorbent assay, were significantly higher in hypertensive patients than in controls (524.51 ± 26.97 vs. 962.92 ± 15.91 pg/mL; P < 0.001). In hypertensive mice [angiotensin II (AngII) treatment for 14 days] and spontaneously hypertensive rats, ANGPTL8 expression was increased and predominantly located in VSMCs. In AngII-treated mice, systolic and diastolic blood pressure in Tagln-Cre-ANGPTL8fl/fl mice were approximately 15-25 mmHg lower than that in ANGPTL8fl/fl mice. AngII-induced vascular remodelling, vascular constriction, and increased expression of cell markers of proliferation (PCNA and Ki67) and migration (MMP-2 and MMP-9) were strikingly attenuated in Tagln-Cre-ANGPTL8fl/fl mice compared with ANGPTL8fl/fl mice. Furthermore, the AngII-induced increase in the heart size, heart weight, heart/body weight ratio, cardiomyocyte cross-sectional area, and collagen deposition was ameliorated in Tagln-Cre-ANGPTL8fl/fl mice compared with ANGPTL8fl/fl mice. In rat artery smooth muscle cells, ANGPTL8-short hairpin RNA decreased intracellular calcium levels and prevented AngII-induced proliferation and migration through the PI3K-Akt pathway, as shown using LY294002 (inhibitor of PI3K) and Akt inhibitor VIII.
CONCLUSION
This study suggests that ANGPTL8 in VSMCs plays an important role in AngII-induced hypertension and associated cardiovascular remodelling. ANGPTL8 may be a novel therapeutic target against pathological hypertension and hypertensive cardiovascular hypertrophy.
Topics: Rats; Mice; Animals; Angiopoietin-Like Protein 8; Muscle, Smooth, Vascular; Angiotensin II; Phosphatidylinositol 3-Kinases; Hypertension; Rats, Inbred SHR; Hypertrophy; Myocytes, Smooth Muscle
PubMed: 37285486
DOI: 10.1093/cvr/cvad089 -
Pharmacology & Therapeutics Nov 2023Severe hypertriglyceridemia (sHTG), defined as a triglyceride (TG) concentration ≥ 500 mg/dL (≥ 5.7 mmol/L) is an important risk factor for acute pancreatitis.... (Review)
Review
Severe hypertriglyceridemia (sHTG), defined as a triglyceride (TG) concentration ≥ 500 mg/dL (≥ 5.7 mmol/L) is an important risk factor for acute pancreatitis. Although lifestyle, some medications, and certain conditions such as diabetes may lead to HTG, sHTG results from a combination of major and minor genetic defects in proteins that regulate TG lipolysis. Familial chylomicronemia syndrome (FCS) is a rare disorder caused by complete loss of function in lipoprotein lipase (LPL) or LPL activating proteins due to two homozygous recessive traits or compound heterozygous traits. Multifactorial chylomicronemia syndrome (MCS) and sHTG are due to the accumulation of rare heterozygous variants and polygenic defects that predispose individuals to sHTG phenotypes. Until recently, treatment of sHTG focused on lifestyle interventions, control of secondary factors, and nonselective pharmacotherapies that had modest TG-lowering efficacy and no corresponding reductions in atherosclerotic cardiovascular disease events. Genetic discoveries have allowed for the development of novel pathway-specific therapeutics targeting LPL modulating proteins. New targets directed towards inhibition of apolipoprotein C-III (apoC-III), angiopoietin-like protein 3 (ANGPTL3), angiopoietin-like protein 4 (ANGPTL4), and fibroblast growth factor-21 (FGF21) offer far more efficacy in treating the various phenotypes of sHTG and opportunities to reduce the risk of acute pancreatitis and atherosclerotic cardiovascular disease events.
Topics: Humans; Acute Disease; Cardiovascular Diseases; Pancreatitis; Hyperlipoproteinemia Type I; Hypertriglyceridemia; Angiopoietin-Like Protein 3
PubMed: 37848164
DOI: 10.1016/j.pharmthera.2023.108544 -
Proceedings of the National Academy of... Jan 2024Leptin protein was thought to be unique to leptin receptor (LepR), but the phenotypes of mice with mutation in LepR [ (diabetes)] and leptin [ (obese)] are not...
Leptin protein was thought to be unique to leptin receptor (LepR), but the phenotypes of mice with mutation in LepR [ (diabetes)] and leptin [ (obese)] are not identical, and the cause remains unclear. Here, we show that , but not , mice had defect in tenotomy-induced heterotopic ossification (HO), implicating alternative ligand(s) for LepR might be involved. Ligand screening revealed that ANGPTL4 (angiopoietin-like protein 4), a stress and fasting-induced factor, was elicited from brown adipose tissue after tenotomy, bound to LepR on PRRX1 mesenchymal cells at the HO site, thus promotes chondrogenesis and HO development. Disruption of LepR in PRRX1 cells, or lineage ablation of LepR cells, or deletion of ANGPTL4 impeded chondrogenesis and HO in mice. Together, these findings identify ANGPTL4 as a ligand for LepR to regulate the formation of acquired HO.
Topics: Animals; Mice; Leptin; Ligands; Mice, Inbred C57BL; Ossification, Heterotopic; Osteogenesis; Receptors, Leptin
PubMed: 38147550
DOI: 10.1073/pnas.2310685120 -
Blood Sep 2023The bone marrow microenvironment (BMM) can regulate leukemia stem cells (LSCs) via secreted factors. Increasing evidence suggests that dissecting the mechanisms by which...
The bone marrow microenvironment (BMM) can regulate leukemia stem cells (LSCs) via secreted factors. Increasing evidence suggests that dissecting the mechanisms by which the BMM maintains LSCs may lead to the development of effective therapies for the eradication of leukemia. Inhibitor of DNA binding 1 (ID1), a key transcriptional regulator in LSCs, previously identified by us, controls cytokine production in the BMM, but the role of ID1 in acute myeloid leukemia (AML) BMM remains obscure. Here, we report that ID1 is highly expressed in the BMM of patients with AML, especially in BM mesenchymal stem cells, and that the high expression of ID1 in the AML BMM is induced by BMP6, secreted from AML cells. Knocking out ID1 in mesenchymal cells significantly suppresses the proliferation of cocultured AML cells. Loss of Id1 in the BMM results in impaired AML progression in AML mouse models. Mechanistically, we found that Id1 deficiency significantly reduces SP1 protein levels in mesenchymal cells cocultured with AML cells. Using ID1-interactome analysis, we found that ID1 interacts with RNF4, an E3 ubiquitin ligase, and causes a decrease in SP1 ubiquitination. Disrupting the ID1-RNF4 interaction via truncation in mesenchymal cells significantly reduces SP1 protein levels and delays AML cell proliferation. We identify that the target of Sp1, Angptl7, is the primary differentially expression protein factor in Id1-deficient BM supernatant fluid to regulate AML progression in mice. Our study highlights the critical role of ID1 in the AML BMM and aids the development of therapeutic strategies for AML.
Topics: Animals; Mice; Angiopoietin-Like Protein 7; Bone Marrow; Disease Models, Animal; Leukemia, Myeloid, Acute; Tumor Microenvironment; Humans; Inhibitor of Differentiation Protein 1
PubMed: 37319434
DOI: 10.1182/blood.2022019537 -
Trends in Cardiovascular Medicine May 2024Optimal management of low-density lipoprotein cholesterol (LDL-C) is a central tenet in the primary and secondary prevention of atherosclerotic cardiovascular disease... (Review)
Review
Optimal management of low-density lipoprotein cholesterol (LDL-C) is a central tenet in the primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD). However, significant residual cardiovascular risk remains despite achieving guideline-directed LDL-C levels, in part due to mixed hyperlipidemia with elevated fasting and non-fasting triglyceride-rich lipoprotein levels. Advances in human genetics have identified angiopoietin-like 3 (ANGPTL3) as a promising therapeutic target to lower cardiovascular risk. Evidence accrued from genetic epidemiological studies demonstrate that ANGPTL3 loss of function is strongly associated with lowering of circulating LDL-C, triglyceride-rich lipoproteins and concurrent risk reduction in development of coronary artery disease. Pharmacological inhibition of ANGPTL3 with monoclonal antibodies, antisense oligonucleotides and gene editing are in development with early studies showing their safety and efficacy in lowering in both, LDL-C and TGs, circumventing a key limitation of previous therapies. Monoclonal antibodies targeting ANGPTL3 are approved for clinical use in homozygous familial hypercholesteremia in USA and Europe. Although promising, future studies focusing on long-term beneficial effect in reducing cardiovascular events with inhibition of ANGPTL3 are warranted.
Topics: Animals; Humans; Angiopoietin-Like Protein 3; Antibodies, Monoclonal; Biomarkers; Cardiovascular Diseases; Cholesterol, LDL; Dyslipidemias; Gene Editing; Genetic Predisposition to Disease; Heart Disease Risk Factors; Hypolipidemic Agents; Molecular Targeted Therapy; Oligonucleotides, Antisense; Treatment Outcome
PubMed: 36746257
DOI: 10.1016/j.tcm.2023.01.008 -
JCI Insight Sep 2023Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), cause severe endothelial dysfunction in the lung, and vascular endothelial...
Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), cause severe endothelial dysfunction in the lung, and vascular endothelial growth factor (VEGF) is elevated in ARDS. We found that the levels of a VEGF-regulated microRNA, microRNA-1 (miR-1), were reduced in the lung endothelium after acute injury. Pulmonary endothelial cell-specific (EC-specific) overexpression of miR-1 protected the lung against cell death and barrier dysfunction in both murine and human models and increased the survival of mice after pneumonia-induced ALI. miR-1 had an intrinsic protective effect in pulmonary and other types of ECs; it inhibited apoptosis and necroptosis pathways and decreased capillary leak by protecting adherens and tight junctions. Comparative gene expression analysis and RISC recruitment assays identified miR-1 targets in the context of injury, including phosphodiesterase 5A (PDE5A), angiopoietin-2 (ANGPT2), CNKSR family member 3 (CNKSR3), and TNF-α-induced protein 2 (TNFAIP2). We validated miR-1-mediated regulation of ANGPT2 in both mouse and human ECs and found that in a 119-patient pneumonia cohort, miR-1 correlated inversely with ANGPT2. These findings illustrate a previously unknown role of miR-1 as a cytoprotective orchestrator of endothelial responses to acute injury with prognostic and therapeutic potential.
Topics: Humans; Animals; Mice; MicroRNAs; Vascular Endothelial Growth Factor A; Acute Lung Injury; Respiratory Distress Syndrome; Endothelium
PubMed: 37737266
DOI: 10.1172/jci.insight.164816 -
Ophthalmology Science Sep 2023Dual inhibition of angiopoietin-2 and VEGF-A with faricimab (Vabysmo) offers excellent visual acuity gains with strong durability in patients with diabetic macular edema...
PURPOSE
Dual inhibition of angiopoietin-2 and VEGF-A with faricimab (Vabysmo) offers excellent visual acuity gains with strong durability in patients with diabetic macular edema (ME) and neovascular age-related macular degeneration. The phase III BALATON/COMINO (NCT04740905/NCT04740931) trials will investigate the efficacy, safety, and durability of faricimab in patients with ME due to retinal vein occlusion (RVO).
DESIGN
Two identically designed global, randomized, double-masked, active comparator-controlled studies.
PARTICIPANTS
Anti-VEGF treatment-naive patients with branch, central, or hemiretinal RVO.
METHODS
Patients were randomized to 6 monthly injections of faricimab 6.0 mg or aflibercept 2.0 mg. From weeks 24 to 72, all patients received faricimab 6.0 mg administered in up to 16-week intervals using an automated treatment algorithm to generate a treat-and-extend-based personalized treatment interval dosing regimen. Personalized treatment interval adjustments were based on changes in central subfield thickness (CST) and best-corrected visual acuity (BCVA).
MAIN OUTCOME MEASURES
Primary end point was noninferiority of faricimab versus aflibercept in mean change from baseline in BCVA (week 24; noninferiority margin: 4 letters). Secondary end points (weeks 0-24) were mean change from baseline in BCVA, CST, and National Eye Institute Visual Function Questionnaire 25 composite score; proportion of patients gaining or avoiding loss of ≥ 15/≥ 10/≥ 5/> 0 letters. Secondary end points (weeks 24-72) were treatment durability (week 68); continuation of weeks 0 to 24 end points. Ocular/nonocular adverse events will be assessed.
RESULTS
In total, 1282 patients across 22 countries were enrolled (BALATON, 553 patients, 149 centers; COMINO, 729 patients, 193 centers).
CONCLUSIONS
Using a novel automated interval algorithm, BALATON/COMINO will evaluate the efficacy and safety of faricimab for ME secondary to RVO and provide key insights into how to personalize treatment.
FINANCIAL DISCLOSURES
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
PubMed: 37810589
DOI: 10.1016/j.xops.2023.100302