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Article ; Online: Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, double-masked, non-inferiority, phase 3 trial.

2024 Volume 403, Issue 10432, Page(s) 1141–1152

Abstract: Background: Intravitreal aflibercept 8 mg could improve treatment outcomes and provide sustained disease control in patients with neovascular age-related macular degeneration (nAMD), with extended dosing compared with aflibercept 2 mg.: Methods: ... ...

Abstract	Background: Intravitreal aflibercept 8 mg could improve treatment outcomes and provide sustained disease control in patients with neovascular age-related macular degeneration (nAMD), with extended dosing compared with aflibercept 2 mg. Methods: PULSAR is a phase 3, randomised, three-group, double-masked, non-inferiority, 96-week trial conducted across 223 sites worldwide. Adults with nAMD were randomised 1:1:1 to aflibercept 8 mg every 12 weeks (8q12), aflibercept 8 mg every 16 weeks (8q16), or aflibercept 2 mg every 8 weeks (2q8), following three initial monthly doses in all groups. From week 16, patients in the aflibercept 8 mg groups had their dosing interval shortened if pre-specified dose regimen modification criteria denoting disease activity were met. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48. All patients with at least one dose of study treatment were included in the efficacy and safety analyses. This trial is registered with ClinicalTrials.gov (NCT04423718) and is ongoing. Findings: Of 1011 patients randomised to aflibercept 8q12 (n=336), 8q16 (n=338), or 2q8 (n=337) between Aug 11, 2020, and July 30, 2021, 1009 patients received study treatment (aflibercept 8q12 n=335; aflibercept 8q16 n=338; and aflibercept 2q8 n=336). Aflibercept 8q12 and 8q16 showed non-inferior BCVA gains versus aflibercept 2q8 (mean BCVA change from baseline +6·7 [SD 12·6] and +6·2 [11·7] vs +7·6 [12·2] letters). The least squares mean differences between aflibercept 8q12 versus 2q8 and 8q16 versus 2q8, respectively, were -0·97 (95% CI -2·87 to 0·92) and -1·14 (-2·97 to 0·69) letters (non-inferiority margin at 4 letters). The incidence of ocular adverse events in the study eye was similar across groups (aflibercept 8q12 n=129 [39%]; aflibercept 8q16 n=127 [38%]; and aflibercept 2q8 n=130 [39%]). Interpretation: Aflibercept 8 mg showed efficacy and safety with extended dosing intervals, which has the potential to improve the management of patients with nAMD. Funding: Bayer AG and Regeneron Pharmaceuticals.
MeSH term(s)	Adult ; Humans ; Angiogenesis Inhibitors/adverse effects ; DEAE-Dextran ; Macular Degeneration/drug therapy ; Receptors, Vascular Endothelial Growth Factor/therapeutic use ; Recombinant Fusion Proteins/adverse effects ; Treatment Outcome
Chemical Substances	aflibercept (15C2VL427D) ; Angiogenesis Inhibitors ; DEAE-Dextran (9015-73-0) ; Receptors, Vascular Endothelial Growth Factor (EC 2.7.10.1) ; Recombinant Fusion Proteins
Language	English
Publishing date	2024-03-07
Publishing country	England
Document type	Clinical Trial, Phase III ; Equivalence Trial ; Journal Article ; Randomized Controlled Trial
ZDB-ID	3306-6
ISSN	1474-547X ; 0023-7507 ; 0140-6736
ISSN (online)	1474-547X
ISSN	0023-7507 ; 0140-6736
DOI	10.1016/S0140-6736(24)00063-1
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Article ; Online: Dupilumab in patients with prurigo nodularis: two randomized, double-blind, placebo-controlled phase 3 trials.

Yosipovitch, Gil / Mollanazar, Nicholas / Ständer, Sonja / Kwatra, Shawn G / Kim, Brian S / Laws, Elizabeth / Mannent, Leda P / Amin, Nikhil / Akinlade, Bolanle / Staudinger, Heribert W / Patel, Naimish / Yancopoulos, George D / Weinreich, David M / Wang, Sheldon / Shi, Genming / Bansal, Ashish / O'Malley, John T

Nature medicine

2023 Volume 29, Issue 5, Page(s) 1180–1190

Abstract: Prurigo nodularis (PN) is a chronic inflammatory skin disease with intensely pruritic nodules. The LIBERTY-PN PRIME and PRIME2 phase 3 trials enrolled adults with PN with ≥20 nodules and severe itch uncontrolled with topical therapies. Dupilumab, a fully ...

Abstract	Prurigo nodularis (PN) is a chronic inflammatory skin disease with intensely pruritic nodules. The LIBERTY-PN PRIME and PRIME2 phase 3 trials enrolled adults with PN with ≥20 nodules and severe itch uncontrolled with topical therapies. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4 and IL-13. Patients were randomized 1:1 to 300 mg dupilumab or placebo subcutaneously every 2 weeks for 24 weeks. The primary endpoint was pruritus improvement, measured by proportion of patients with a ≥4-point reduction in Worst Itch Numeric Rating Scale (WI-NRS) from baseline at week 24 (PRIME) or week 12 (PRIME2). Key secondary endpoints included nodule number reduction to ≤5 at week 24. PRIME and PRIME2 enrolled 151 and 160 patients, respectively. Both trials met all the pre-specified primary and key secondary endpoints. A ≥4-point WI-NRS reduction at week 24 in the dupilumab and placebo arms was achieved by 60.0% and 18.4% of patients, respectively, in PRIME (95% confidence interval (CI), 27.8-57.7 for the difference, P < 0.001) and at week 12 by 37.2% and 22.0% of patients, respectively, in PRIME2 (95% CI, 2.3-31.2; P = 0.022). Dupilumab demonstrated clinically meaningful and statistically significant improvements in itch and skin lesions versus placebo in PN. Safety was consistent with the known dupilumab safety profile.ClinicalTrials.gov identifiers: NCT04183335 and NCT04202679 .
MeSH term(s)	Adult ; Humans ; Prurigo/drug therapy ; Severity of Illness Index ; Injections, Subcutaneous ; Treatment Outcome ; Pruritus/drug therapy ; Double-Blind Method ; Chronic Disease
Chemical Substances	dupilumab (420K487FSG)
Language	English
Publishing date	2023-05-04
Publishing country	United States
Document type	Randomized Controlled Trial ; Clinical Trial, Phase III ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/s41591-023-02320-9
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Zs.A 4212: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Glucagon orchestrates stress-induced hyperglycaemia.

Harp, J B / Yancopoulos, G D / Gromada, J

Diabetes, obesity & metabolism

2016 Volume 18, Issue 7, Page(s) 648–653

Abstract: Hyperglycaemia is commonly observed on admission and during hospitalization for medical illness, traumatic injury, burn and surgical intervention. This transient hyperglycaemia is referred to as stress-induced hyperglycaemia (SIH) and frequently occurs ... ...

Abstract	Hyperglycaemia is commonly observed on admission and during hospitalization for medical illness, traumatic injury, burn and surgical intervention. This transient hyperglycaemia is referred to as stress-induced hyperglycaemia (SIH) and frequently occurs in individuals without a history of diabetes. SIH has many of the same underlying hormonal disturbances as diabetes mellitus, specifically absolute or relative insulin deficiency and glucagon excess. SIH has the added features of elevated blood levels of catecholamines and cortisol, which are not typically present in people with diabetes who are not acutely ill. The seriousness of SIH is highlighted by its greater morbidity and mortality rates compared with those of hospitalized patients with normal glucose levels, and this increased risk is particularly high in those without pre-existing diabetes. Insulin is the treatment standard for SIH, but new therapies that reduce glucose variability and hypoglycaemia are desired. In the present review, we focus on the key role of glucagon in SIH and discuss the potential use of glucagon receptor blockers and glucagon-like peptide-1 receptor agonists in SIH to achieve target glucose control.
MeSH term(s)	Diabetes Mellitus, Type 1/physiopathology ; Diabetes Mellitus, Type 2/physiopathology ; Glucagon/metabolism ; Glucagon/physiology ; Glucagon-Like Peptide-1 Receptor/agonists ; Glucagon-Like Peptide-1 Receptor/antagonists & inhibitors ; Humans ; Hyperglycemia/drug therapy ; Hyperglycemia/etiology ; Hyperglycemia/physiopathology ; Stress, Physiological/physiology
Chemical Substances	Glucagon-Like Peptide-1 Receptor ; Glucagon (9007-92-5)
Language	English
Publishing date	2016-05-04
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1454944-x
ISSN	1463-1326 ; 1462-8902
ISSN (online)	1463-1326
ISSN	1462-8902
DOI	10.1111/dom.12668
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Article: CLL stereotyped B-cell receptor immunoglobulin sequences are recurrent in the B-cell repertoire of healthy individuals: Apparent lack of central and early peripheral tolerance censoring.

Vergani, Stefano / Bagnara, Davide / Agathangelidis, Andreas / Ng, Anita Kar Yun / Ferrer, Gerardo / Mazzarello, Andrea N / Palacios, Florencia / Yancopoulos, Sophia / Yan, Xiao-Jie / Barrientos, Jaqueline C / Rai, Kanti R / Stamatopoulos, Kostas / Chiorazzi, Nicholas

Frontiers in oncology

2023 Volume 13, Page(s) 1112879

Abstract: Introduction: The leukemic cells of patients with chronic lymphocytic leukemia (CLL) are often unique, expressing remarkably similar IGHV-IGHD-IGHJ gene rearrangements, "stereotyped BCRs". The B-cell receptors (BCRs) on CLL cells are also distinctive in ...

Abstract	Introduction: The leukemic cells of patients with chronic lymphocytic leukemia (CLL) are often unique, expressing remarkably similar IGHV-IGHD-IGHJ gene rearrangements, "stereotyped BCRs". The B-cell receptors (BCRs) on CLL cells are also distinctive in often deriving from autoreactive B lymphocytes, leading to the assumption of a defect in immune tolerance. Results: Using bulk and single-cell immunoglobulin heavy and light chain variable domain sequencing, we enumerated CLL stereotype-like IGHV-IGHD-IGHJ sequences (CLL-SLS) in B cells from cord blood (CB) and adult peripheral blood (PBMC) and bone marrow (BM of healthy donors. CLL-SLS were found at similar frequencies among CB, BM, and PBMC, suggesting that age does not influence CLL-SLS levels. Moreover, the frequencies of CLL-SLS did not differ among B lymphocytes in the BM at early stages of development, and only re-circulating marginal zone B cells contained significantly higher CLL-SLS frequencies than other mature B-cell subpopulations. Although we identified CLL-SLS corresponding to most of the CLL major stereotyped subsets, CLL-SLS frequencies did not correlate with those found in patients. Interestingly, in CB samples, half of the CLL-SLS identified were attributed to two IGHV-mutated subsets. We also found satellite CLL-SLS among the same normal samples, and they were also enriched in naïve B cells but unexpectedly, these were ~10-fold higher than standard CLL-SLS. In general, IGHV-mutated CLL-SLS subsets were enriched among antigen-experienced B-cell subpopulations, and IGHV-unmutated CLL-SLS were found mostly in antigen-inexperienced B cells. Nevertheless, CLL-SLS with an IGHV-mutation status matching that of CLL clones varied among the normal B-cell subpopulations, suggesting that specific CLL-SLS could originate from distinct subpopulations of normal B cells. Lastly, using single-cell DNA sequencing, we identified paired IGH and IGL rearrangements in normal B lymphocytes resembling those of stereotyped BCRs in CLL, although some differed from those in patients based on IG isotype or somatic mutation. Discussion: CLL-SLS are present in normal B-lymphocyte populations at all stages of development. Thus, despite their autoreactive profile they are not deleted by central tolerance mechanisms, possibly because the level of autoreactivity is not registered as dangerous by deletion mechanisms or because editing of L-chain variable genes occurred which our experimental approach could not identify.
Language	English
Publishing date	2023-03-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2023.1112879
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Article ; Online: Effect of High-Dose Intravitreal Aflibercept, 8 mg, in Patients With Neovascular Age-Related Macular Degeneration: The Phase 2 CANDELA Randomized Clinical Trial.

Wykoff, Charles C / Brown, David M / Reed, Kimberly / Berliner, Alyson J / Gerstenblith, Adam T / Breazna, Aurora / Abraham, Prema / Fein, Jordana G / Chu, Karen W / Clark, W Lloyd / Leal, Sergio / Schmelter, Thomas / Hirshberg, Boaz / Yancopoulos, George D / Vitti, Robert

JAMA ophthalmology

2023 Volume 141, Issue 9, Page(s) 834–842

Abstract: Importance: Aflibercept, 8 mg, may have greater therapeutic benefits compared with aflibercept, 2 mg, in patients with neovascular age-related macular degeneration (nAMD), including potentially improved outcomes and decreased treatment burden.: ... ...

Abstract	Importance: Aflibercept, 8 mg, may have greater therapeutic benefits compared with aflibercept, 2 mg, in patients with neovascular age-related macular degeneration (nAMD), including potentially improved outcomes and decreased treatment burden. Objective: To assess safety and efficacy of aflibercept, 8 mg, in patients with nAMD. Design, setting, and participants: The CANDELA trial was a phase 2, randomized, single-masked, open-label, 44-week clinical trial conducted in the US. Treatment-naive patients with active subfoveal choroidal neovascularization secondary to nAMD and a best-corrected visual acuity score of 78 to 24 letters (approximately 20/32 to 20/320) in the study eye were enrolled between November 2019 and November 2021. Interventions: Eligible participants were randomized 1:1 to receive 3 monthly doses of 8 mg (70 μL) or 2 mg (50 μL) of aflibercept followed by doses at weeks 20 and 32. Main outcomes and measures: Coprimary end points were the proportion of eyes without fluid (absence of intraretinal and subretinal fluid) in the central subfield at week 16 and safety. Results: All 106 eligible eyes were randomized to receive aflibercept, 8 mg (n = 53), or aflibercept, 2 mg (n = 53). Overall, 66 participants (62.3%) were female. The proportion of eyes without fluid in the central subfield with 8-mg vs 2-mg aflibercept was 50.9% (n = 27) vs 34.0% (n = 18) (difference, 17.0 [95% CI, -1.6 to 35.5] percentage points; P = .08) at week 16 and 39.6% (n = 21) vs 28.3% (n = 15) (difference, 11.3 [95% CI, -6.6 to 29.2] percentage points; nominal P = .22) at week 44. At week 44, mean (SE) change in central retinal thickness was -159.4 (16.4) vs -137.2 (22.8) μm with 8 mg vs 2 mg of aflibercept, respectively (least squares mean difference, -9.5 [95% CI, -51.4 to 32.4]; nominal P = .65) and mean (SE) change in best-corrected visual acuity score was +7.9 (1.5) vs +5.1 (1.5) letters (least squares mean difference, +2.8 [95% CI, -1.4 to +7.0]; nominal P = .20). No differences in safety profiles between the groups were observed. Conclusions and relevance: Although aflibercept, 8 mg, did not achieve the primary efficacy end point at week 16 at the 2-sided significance level of 5%, the observed trends in anatomic and visual improvements over 44 weeks with aflibercept, 8 mg, indicate potential additional therapeutic benefit over aflibercept, 2 mg. No new safety signals were observed over 44 weeks. These findings support further evaluation of aflibercept, 8 mg, in pivotal trials of exudative retinal diseases including nAMD and diabetic macular edema. Trial registration: ClinicalTrials.gov Identifier: NCT04126317.
MeSH term(s)	Humans ; Female ; Male ; Angiogenesis Inhibitors/therapeutic use ; Diabetic Retinopathy/drug therapy ; Macular Edema/drug therapy ; Receptors, Vascular Endothelial Growth Factor/therapeutic use ; Recombinant Fusion Proteins/adverse effects
Chemical Substances	Angiogenesis Inhibitors ; aflibercept (15C2VL427D) ; Receptors, Vascular Endothelial Growth Factor (EC 2.7.10.1) ; Recombinant Fusion Proteins
Language	English
Publishing date	2023-08-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701705-9
ISSN	2168-6173 ; 2168-6165
ISSN (online)	2168-6173
ISSN	2168-6165
DOI	10.1001/jamaophthalmol.2023.2421
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Article ; Online: A cellular and molecular spatial atlas of dystrophic muscle.

Stec, Michael J / Su, Qi / Adler, Christina / Zhang, Lance / Golann, David R / Khan, Naveen P / Panagis, Lampros / Villalta, S Armando / Ni, Min / Wei, Yi / Walls, Johnathon R / Murphy, Andrew J / Yancopoulos, George D / Atwal, Gurinder S / Kleiner, Sandra / Halasz, Gabor / Sleeman, Mark W

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 29, Page(s) e2221249120

Abstract: Asynchronous skeletal muscle degeneration/regeneration is a hallmark feature of Duchenne muscular dystrophy (DMD); however, traditional -omics technologies that lack spatial context make it difficult to study the biological mechanisms of how asynchronous ...

Abstract	Asynchronous skeletal muscle degeneration/regeneration is a hallmark feature of Duchenne muscular dystrophy (DMD); however, traditional -omics technologies that lack spatial context make it difficult to study the biological mechanisms of how asynchronous regeneration contributes to disease progression. Here, using the severely dystrophic D2-mdx mouse model, we generated a high-resolution cellular and molecular spatial atlas of dystrophic muscle by integrating spatial transcriptomics and single-cell RNAseq datasets. Unbiased clustering revealed nonuniform distribution of unique cell populations throughout D2-mdx muscle that were associated with multiple regenerative timepoints, demonstrating that this model faithfully recapitulates the asynchronous regeneration observed in human DMD muscle. By probing spatiotemporal gene expression signatures, we found that propagation of inflammatory and fibrotic signals from locally damaged areas contributes to widespread pathology and that querying expression signatures within discrete microenvironments can identify targetable pathways for DMD therapy. Overall, this spatial atlas of dystrophic muscle provides a valuable resource for studying DMD disease biology and therapeutic target discovery.
MeSH term(s)	Animals ; Mice ; Humans ; Muscle, Skeletal/metabolism ; Mice, Inbred mdx ; Muscular Dystrophy, Duchenne/metabolism ; Disease Progression ; Disease Models, Animal
Language	English
Publishing date	2023-07-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2221249120
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Zs.A 1148: Show issues

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Article ; Online: Activin E-ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice.

Adam, Rene C / Pryce, Dwaine S / Lee, Joseph S / Zhao, Yuanqi / Mintah, Ivory J / Min, Soo / Halasz, Gabor / Mastaitis, Jason / Atwal, Gurinder S / Aykul, Senem / Idone, Vincent / Economides, Aris N / Lotta, Luca A / Murphy, Andrew J / Yancopoulos, George D / Sleeman, Mark W / Gusarova, Viktoria

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 32, Page(s) e2309967120

Abstract: Body fat distribution is a heritable risk factor for cardiovascular and metabolic disease. In humans, rare Inhibin beta E ( ...

Abstract	Body fat distribution is a heritable risk factor for cardiovascular and metabolic disease. In humans, rare Inhibin beta E (
MeSH term(s)	Humans ; Mice ; Animals ; Lipolysis ; Activins/metabolism ; Adiposity/genetics ; Diabetes Mellitus, Type 2/metabolism ; PPAR gamma/metabolism ; Obesity/metabolism ; Adipose Tissue/metabolism ; Activin Receptors, Type I/genetics ; Activin Receptors, Type I/metabolism
Chemical Substances	Activins (104625-48-1) ; PPAR gamma ; ACVR1C protein, human (EC 2.7.11.30) ; Activin Receptors, Type I (EC 2.7.11.30)
Language	English
Publishing date	2023-07-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2309967120
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Article ; Online: Evaluating the efficacy and safety of pozelimab in patients with CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy disease: an open-label phase 2 and 3 study.

Ozen, Ahmet / Chongsrisawat, Voranush / Sefer, Asena Pinar / Kolukisa, Burcu / Jalbert, Jessica J / Meagher, Karoline A / Brackin, Taylor / Feldman, Hagit Baris / Baris, Safa / Karakoc-Aydiner, Elif / Ergelen, Rabia / Fuss, Ivan J / Moorman, Heather / Suratannon, Narissara / Suphapeetiporn, Kanya / Perlee, Lorah / Harari, Olivier A / Yancopoulos, George D / Lenardo, Michael J

Lancet (London, England)

2024 Volume 403, Issue 10427, Page(s) 645–656

Abstract: ... at baseline was 2·2 g/dL, which was considerably less than the local laboratory reference range. After ...

Abstract	Background: CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) is an ultra-rare genetic disorder characterised by intestinal lymphatic damage, lymphangiectasia, and protein-losing enteropathy caused by overactivation of the complement system. We assessed the efficacy and safety of pozelimab, an antibody blocking complement component 5. Methods: This open-label, single-arm, historically controlled, multicentre phase 2 and 3 study evaluated ten patients with CHAPLE disease. This study was conducted at three hospitals in Thailand, Türkiye, and the USA. Patients aged 1 year or older with a clinical diagnosis of CHAPLE disease and a CD55 loss-of-function variant identified by genetic analysis and confirmed by flow cytometry or western blot of CD55 from peripheral blood cells were eligible for this study. Patients received a single intravenous loading dose of pozelimab 30 mg per kg of bodyweight, followed by a once-per-week subcutaneous dose over the treatment period based on bodyweight at a concentration of 200 mg/mL as either a single injection (<40 kg bodyweight) or two injections (≥40 kg bodyweight). The primary endpoint was proportion of patients with serum albumin normalisation with an improvement in active clinical outcomes and no worsening in inactive clinical outcomes (frequency of problematic abdominal pain, bowel movement frequency, facial oedema severity, and peripheral oedema severity) at week 24 compared with baseline, assessed in the full analysis set. This study is registered with ClinicalTrials.gov (NCT04209634) and is active but not recruiting. Findings: 11 patients were recruited between Jan 27, 2020, and May 12, 2021, ten of which were enrolled in the study and included in the analysis populations. The efficacy data corresponded to all patients completing the week 48 assessment and having at least 52 weeks of treatment exposure, and the safety data included an additional 90 days of follow-up and corresponded to all patients having at least 72 weeks of treatment. Patients were predominantly paediatric (with a median age of 8·5 years), and originated from Türkiye, Syria, Thailand, and Bolivia. Patients had markedly low weight-for-age and stature-for-age at baseline, and mean albumin at baseline was 2·2 g/dL, which was considerably less than the local laboratory reference range. After pozelimab treatment, all ten patients had serum albumin normalisation and improvement with no worsening in clinical outcomes. There was a complete inhibition of the total complement activity. Nine patients had adverse events; two were severe events, and one patient had an adverse event considered related to pozelimab. Interpretation: Pozelimab inhibits complement overactivation and resolves the clinical and laboratory manifestations of CHAPLE disease. Pozelimab is the only currently approved therapeutic drug for patients with this life-threatening, ultra-rare condition. In patients with protein-losing enteropathy where known causes have been excluded, testing for a CD55 deficiency should be contemplated. A diagnosis of CHAPLE disease should lead to early consideration of treatment with pozelimab. Funding: Regeneron Pharmaceuticals and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
MeSH term(s)	Child ; Humans ; Antibodies, Monoclonal ; Edema ; Protein-Losing Enteropathies/drug therapy ; Serum Albumin ; Thrombosis ; Treatment Outcome ; Historically Controlled Study ; Male ; Female
Chemical Substances	Antibodies, Monoclonal ; Serum Albumin
Language	English
Publishing date	2024-01-23
Publishing country	England
Document type	Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Multicenter Study
ZDB-ID	3306-6
ISSN	1474-547X ; 0023-7507 ; 0140-6736
ISSN (online)	1474-547X
ISSN	0023-7507 ; 0140-6736
DOI	10.1016/S0140-6736(23)02358-9
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Article ; Online: Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial.

Gogishvili, Miranda / Melkadze, Tamar / Makharadze, Tamta / Giorgadze, Davit / Dvorkin, Mikhail / Penkov, Konstantin / Laktionov, Konstantin / Nemsadze, Gia / Nechaeva, Marina / Rozhkova, Irina / Kalinka, Ewa / Gessner, Christian / Moreno-Jaime, Brizio / Passalacqua, Rodolfo / Li, Siyu / McGuire, Kristina / Kaul, Manika / Paccaly, Anne / Quek, Ruben G W /

Gao, Bo / Seebach, Frank / Weinreich, David M / Yancopoulos, George D / Lowy, Israel / Gullo, Giuseppe / Rietschel, Petra

Nature medicine

2022 Volume 28, Issue 11, Page(s) 2374–2380

Abstract: First-line cemiplimab (anti-programmed cell death-1 (PD-1)) monotherapy has previously shown significant improvement in overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with advanced non-small cell lung cancer ( ... ...

Abstract	First-line cemiplimab (anti-programmed cell death-1 (PD-1)) monotherapy has previously shown significant improvement in overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with advanced non-small cell lung cancer (aNSCLC) and PD-ligand 1 (PD-L1) expression ≥50%. EMPOWER-Lung 3 ( NCT03409614 ), a double-blind, placebo-controlled, phase 3 study, examined cemiplimab plus platinum-doublet chemotherapy as first-line treatment for aNSCLC, irrespective of PD-L1 expression or histology. In this study, 466 patients with stage III/IV aNSCLC without EGFR, ALK or ROS1 genomic tumor aberrations were randomized (2:1) to receive cemiplimab 350 mg (n = 312) or placebo (n = 154) every 3 weeks for up to 108 weeks in combination with four cycles of platinum-doublet chemotherapy (followed by pemetrexed maintenance as indicated). In total, 57.1% (266/466 patients) had non-squamous NSCLC, and 85.2% (397/466 patients) had stage IV disease. The primary endpoint was OS. The trial was stopped early per recommendation of the independent data monitoring committee, based on meeting preset OS efficacy criteria: median OS was 21.9 months (95% confidence interval (CI), 15.5-not evaluable) with cemiplimab plus chemotherapy versus 13.0 months (95% CI, 11.9-16.1) with placebo plus chemotherapy (hazard ratio (HR) = 0.71; 95% CI, 0.53-0.93; P = 0.014). Grade ≥3 adverse events occurred with cemiplimab plus chemotherapy (43.6%, 136/312 patients) and placebo plus chemotherapy (31.4%, 48/153 patients). Cemiplimab is only the second anti-PD-1/PD-L1 agent to show efficacy in aNSCLC as both monotherapy and in combination with chemotherapy for both squamous and non-squamous histologies.
MeSH term(s)	Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/pathology ; B7-H1 Antigen/therapeutic use ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Platinum/therapeutic use ; Protein-Tyrosine Kinases/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Disease-Free Survival ; Proto-Oncogene Proteins ; Double-Blind Method
Chemical Substances	cemiplimab (6QVL057INT) ; B7-H1 Antigen ; Platinum (49DFR088MY) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Proto-Oncogene Proteins
Language	English
Publishing date	2022-08-25
Publishing country	United States
Document type	Randomized Controlled Trial ; Clinical Trial, Phase III ; Journal Article
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/s41591-022-01977-y
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Article ; Online: Compassionate Use of REGEN-COV® in Patients With Coronavirus Disease 2019 (COVID-19) and Immunodeficiency-Associated Antibody Disorders.

Stein, David / Oviedo-Orta, Ernesto / Kampman, Wendy A / McGinniss, Jennifer / Betts, George / McDermott, Margaret / Holly, Beth / Lancaster, Johnathan M / Braunstein, Ned / Yancopoulos, George D / Weinreich, David M

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

2021 Volume 75, Issue 1, Page(s) e509–e515

Abstract: Background: Patients with immunodeficiency-associated antibody disorders are at a higher risk of prolonged/persistent COVID-19 infection, having no viable treatment options.: Methods: A retrospective analysis of patients with primary and/or secondary ...

Abstract	Background: Patients with immunodeficiency-associated antibody disorders are at a higher risk of prolonged/persistent COVID-19 infection, having no viable treatment options. Methods: A retrospective analysis of patients with primary and/or secondary immunodeficiency-associated antibody disorders who received casirivimab and imdevimab (REGEN-COV®) under emergency compassionate use. Objective were to describe safety and response to REGEN-COV, focusing on the subset of patients who had COVID-19 duration ≥21 days before treatment. Results: Quantitative (change in oxygenation status and/or viral load) and/or qualitative (physician-reported clinical status) outcomes data are reported from 64 patients. Improvement in ≥1 outcome was observed in 90.6% of the overall patient group. Thirty-seven of these had COVID-19 duration ≥21 days before treatment; median time from diagnosis to REGEN-COV treatment was 60.5 days. Of the 29 patients with COVID-19 duration ≥21 days before treatment and available outcome data, 96.6% showed improvement in ≥1 outcome. In the 14 patients with post-treatment reverse transcription-polymerase chain reaction (RT-PCR) results available, 11 (78.6%) reported a negative RT-PCR following treatment, with 5 (45.5%) and 8 (72.7%) patients reporting a negative RT-PCR within 5 days and 21 days of treatment, respectively. Ten of 85 patients (11.8%) experienced serious adverse events; only one was an infusion-related reaction, possibly related to REGEN-COV. Two deaths were reported; neither were attributed to REGEN-COV. Conclusions: In this retrospective analysis of immunodeficient patients granted REGEN-COV under emergency compassionate use, REGEN-COV treatment was associated with rapid viral clearance and clinical improvement in patients with longstanding COVID-19. Adverse events were consistent with COVID-19 and its associated complications, and due to patients' concurrent medical conditions.
MeSH term(s)	Antibodies, Monoclonal, Humanized ; Antibodies, Neutralizing ; COVID-19/drug therapy ; Compassionate Use Trials ; Drug Combinations ; Humans ; Retrospective Studies ; SARS-CoV-2
Chemical Substances	Antibodies, Monoclonal, Humanized ; Antibodies, Neutralizing ; Drug Combinations ; casirivimab and imdevimab drug combination ; imdevimab (2Z3DQD2JHM) ; casirivimab (J0FI6WE1QN)
Language	English
Publishing date	2021-12-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1099781-7
ISSN	1537-6591 ; 1058-4838
ISSN (online)	1537-6591
ISSN	1058-4838
DOI	10.1093/cid/ciab1059
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