DOCSLIB.ORG

Therapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Therapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities REVIEW www.jasn.org Therapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities Chelsea C. Estrada,1 Alejandro Maldonado,1 and Sandeep K. Mallipattu1,2 1Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York; and 2Renal Section, Northport Veterans Affairs Medical Center, Northport, New York ABSTRACT Inhibition of vascular endothelial growth factor A (VEGFA)/vascular endothelial with hypertension and proteinuria. Re- growth factor receptor 2 (VEGFR2) signaling is a common therapeutic strategy in ports describe histologic changes in the oncology, with new drugs continuously in development. In this review, we consider kidney primarily as glomerular endothe- the experimental and clinical evidence behind the diverse nephrotoxicities associ- lial injury with thrombotic microangiop- ated with the inhibition of this pathway. We also review the renal effects of VEGF athy (TMA).8 Nephrotic syndrome has inhibition’s mediation of key downstream signaling pathways, specifically MAPK/ also been observed,9 with the clinical ERK1/2, endothelial nitric oxide synthase, and mammalian target of rapamycin manifestations varying according to (mTOR). Direct VEGFA inhibition via antibody binding or VEGF trap (a soluble decoy mechanism and direct target of VEGF receptor) is associated with renal-specific thrombotic microangiopathy (TMA). Re- inhibition. ports also indicate that tyrosine kinase inhibition of the VEGF receptors is prefer- Current VEGF inhibitors can be clas- entially associated with glomerulopathies such as minimal change disease and FSGS. sifiedbytheirtargetofactioninthe Inhibition of the downstream pathway RAF/MAPK/ERK has largely been associated VEGFA-VEGFR2 pathway: drugs that with tubulointerstitial injury. Inhibition of mTOR is most commonly associated with bind to VEGFA, sequester VEGFA, in- albuminuria and podocyte injury, but has also been linked to renal-specificTMA.In hibit receptor tyrosine kinases (RTKs), all, we review the experimentally validated mechanisms by which VEGFA-VEGFR2 or inhibit downstream pathways. A crit- inhibitors contribute to nephrotoxicity, as well as the wide range of clinical manifes- ical review of VEGFA-VEGFR2 signaling tations that have been reported with their use. We also highlight potential avenues in the kidney is necessary to fully under- for future research to elucidate mechanisms for minimizing nephrotoxicity while standthe mechanismsresponsible for the maintaining therapeutic efficacy. nephrotoxicity associated with the onco- logical use of VEGF inhibition. J Am Soc Nephrol 30: 187–200, 2019. doi: https://doi.org/10.1681/ASN.2018080853 VEGF SIGNALING IN THE KIDNEY Inhibitors of vascular development were of bevacizumab, a recombinant IgG Filtration of plasma in nephrons occurs fi rst investigated as potential chemother- mAb against VEGFA, inhibiting VEGF in the glomerular capillary beds at the fi apeutic agents on the basis of study nd- signaling proved to be a promising ap- glomerular filtration barrier, which con- ings from the late 20th century regarding proach to halting neoplastic develop- sists of three layers: fenestrated endothe- 5 the critical role of angiogenesis in tumor ment. Since then, many additional lial cells, basement membrane, and the development and growth.1 Subsequent agents that block VEGF signaling and investigations led to the discovery of its downstream pathways have become vascular endothelial growth factor A available for the treatment of various (VEGFA), an essential growth factor cancers (Figure 1, i–vi). Published online ahead of print. Publication date for angiogenesis.2,3 Previous studies by Although these agents offer substan- available at www.jasn.org. Kim et al.4 used murine cancer cell lines tial benefit, both in the treatment of Correspondence: Dr. Sandeep K. Mallipattu, Department to show that treatment with an mAb many solid tumors6 as well as age- of Medicine/Nephrology, Stony Brook University, 100 Nicolls Road, HSCT16-80E, Stony Brook, NY 11794- 7 against VEGFA decreased tumor growth, related macular degeneration, their use 8176. Email: sandeep.mallipattu@stonybrookmedicine. indicating a potential therapeutic role is associated with significant nephrotoxi- edu 8 for VEGFA inhibition in cancer treat- city. Most commonly, pharmacologic Copyright © 2019 by the American Society of ment. Beginning with the development VEGF inhibition has been associated Nephrology J Am Soc Nephrol 30: 187–200, 2019 ISSN : 1046-6673/3002-187 187 REVIEW www.jasn.org P P i. VEGFA Ab VEGFA (Bevacizumab, ii. VEGF Trap Ranibizumab) (Aflibercept) GEnC iii. VEGFR2 Ab (Ramucirumab) GBM FP VEGFR2 iv. Tyrosine Kinase Inhibitors (Axitinib, FP Tesevatinib, Nintedanib, Sunitinib) RAS/MAPK/ ERK Pathways v. BRAF Inhibitors GEnC BRAF EF (Vemurafenib, Pl3 Kinase/ Dabrafenib) AKT Pathways eNOS MTORC1 vi. mTOR Inhibitors EF (Temsirolimus, Ridaforolimus, Everolimus) Figure 1. VEGFA-VEGFR2 signaling pathways and their pharmacological inhibition occur across the glomerular filtration barrier. VEGFA is released from podocytes and binds to its receptor (VEGFR2) on glomerular endothelial cells. (i) Bevacizumab and ranibizumab are mAbs against VEGFA and inhibit angiogenesis through IgG antibody interaction with all of its isoforms. (ii) Aflibercept is a recombinant fusion protein comprising binding domains for VEGFR1 and VEGFR2 attached to the Fc portion of human IgG1, and acts as a soluble decoy receptor or “VEGF trap.” (iii) Ramucirumab is a fully humanized IgG1 mAb that specifically inhibits VEGFR2 by targeting its extracellular domain. (iv) TKIs such as sunitinib, pazopanib, sorafenib, and axitinib target VEGFR2, as well as interfere with the activity of additional RTKs such as PDGF receptor, fibroblast growth factor receptor, and EGF receptor, which all share a similar structure. (v) Agents such as vemurafenib and dabrafenib have been recently developed to specifically target B-Raf, a component of the intracellular MAPK/ERK intracellular pathway. (vi) mTOR inhibitors such as temsirolimus, ridaforolimus, and everolimus are used across several malignancies and act downstream of the phosphatidylinositide 3-kinase (PI3K)/AKT signal transduction pathway. Ab, antibody; BRAF, B-Raf Proto-Oncogene; EF, endothelial fenestrations; FP, foot process; GBM, glomerular basement membrane; GEnC, glomerular endothelial cell; P, Podocyte. foot processes of visceral epithelial cells form, which acts as a decoy receptor, in- wide range of glomerulopathies (Table 1) or podocytes. In the kidney, VEGFA is hibiting VEGFA signaling,17 and is the sole demonstrates that tight regulation of expressed by both podocytes10 and renal receptor for VEGFB.12 VEGFA signaling in the kidney is critical tubular epithelial cells11;inhumans, The functional diversity of VEGF re- to glomerular development and the main- VEGFA165 is the most abundant iso- ceptors was initially elucidated by the tenance of mature glomerular function in form.12 VEGFA binds to one of two creation of knockout mice. Mice defi- both homeostasis and disease. For example, RTKs, VEGFR1 and VEGFR213; although cient in Veg fr2 die in utero from a defect knockout of Veg fa during embryogenesis— both receptors have been identified as in hematopoietic and endothelial cell de- including global homozygous or heterozy- playing an important role in angiogenesis, velopment18; embryonic lethality of gous knockout22,23 or podocyte-specific VEGFR2 has been more extensively stud- Veg fr1 deletion is caused by endothelial knockout10—is uniformly lethal at or be- ied, as it is responsible for a majority of cell overgrowth and disorganization.19 fore birth. Mice with podocyte-specificpar- VEGFA signaling and is abundantly dis- These whole-body knockout mice un- tial deletion of Veg fa survive the perinatal tributed in stromal and malignant vascular derscore the key role of VEGF signaling period, but develop endotheliosis and renal tissues.14,15 Both receptors are primarily in endothelial cell proliferation, migra- failure by 9 weeks of age.10 localized in the glomerular and peritubu- tion, and permeability.20 In adult mice, inducible podocyte-specific lar capillary endothelium.11,16 Further- The association of VEGFA overex- Veg fa deletion produces renal-specific more, VEGFR1 also exists in a soluble pression10 or reduction8,21,10 with a TMA, which recapitulates kidney biopsy 188 Journal of the American Society of Nephrology J Am Soc Nephrol 30: 187–200, 2019 www.jasn.org REVIEW Table 1. Renal manifestations in VEGF-VEGFR transgenic murine models Genotype Model Effects Reference 2 2 Vegfa / Constitutive, whole-body Embryonically lethal 22,23 deletion of Vegfa 1 2 Vegfa / Constitutive, whole-body partial Embryonically lethal between days 11 22,23 deletion of Vegfa and 12; defective yolk sac blood supply 2 2 Vegfr1 / Constitutive, whole-body Embryonically lethal because of 19 deletion of Vegfr1 endothelial cell overgrowth and disorganization 2 2 Vegfr2 / Constitutive, whole-body Embryonically lethal because of defect in 18 deletion of Vegfr2 hematopoietic and endothelial cell development Nephrin-Cre; Vegfaflox/flox Constitutive deletion of Vegfa Perinatally lethal, mice die at birth or 10 from podocytes within 18 h with small glomeruli with few capillary loops 1 Nephrin-Cre; Vegfaflox/ Constitutive, partial deletion of Vegfa Endotheliosis, with eventual 10 from podocytes glomerulosclerosis and ESRD by 9–12 wk of age Podocin-rtTA; Doxycycline-inducible deletion of Vegfa Renal thrombotic microangiopathy 8 TetO-Cre; Vegfaflox/flox in podocytes Pax8-rtTA;
Load more

Recommended publications
  • DRUGS REQUIRING PRIOR AUTHORIZATION in the MEDICAL BENEFIT Page 1
    Effective Date: 08/01/2021 DRUGS REQUIRING PRIOR AUTHORIZATION IN THE MEDICAL BENEFIT Page 1 Therapeutic Category Drug Class Trade Name Generic Name HCPCS Procedure Code HCPCS Procedure Code Description Anti-infectives Antiretrovirals, HIV CABENUVA cabotegravir-rilpivirine C9077 Injection, cabotegravir and rilpivirine, 2mg/3mg Antithrombotic Agents von Willebrand Factor-Directed Antibody CABLIVI caplacizumab-yhdp C9047 Injection, caplacizumab-yhdp, 1 mg Cardiology Antilipemic EVKEEZA evinacumab-dgnb C9079 Injection, evinacumab-dgnb, 5 mg Cardiology Hemostatic Agent BERINERT c1 esterase J0597 Injection, C1 esterase inhibitor (human), Berinert, 10 units Cardiology Hemostatic Agent CINRYZE c1 esterase J0598 Injection, C1 esterase inhibitor (human), Cinryze, 10 units Cardiology Hemostatic Agent FIRAZYR icatibant J1744 Injection, icatibant, 1 mg Cardiology Hemostatic Agent HAEGARDA c1 esterase J0599 Injection, C1 esterase inhibitor (human), (Haegarda), 10 units Cardiology Hemostatic Agent ICATIBANT (generic) icatibant J1744 Injection, icatibant, 1 mg Cardiology Hemostatic Agent KALBITOR ecallantide J1290 Injection, ecallantide, 1 mg Cardiology Hemostatic Agent RUCONEST c1 esterase J0596 Injection, C1 esterase inhibitor (recombinant), Ruconest, 10 units Injection, lanadelumab-flyo, 1 mg (code may be used for Medicare when drug administered under Cardiology Hemostatic Agent TAKHZYRO lanadelumab-flyo J0593 direct supervision of a physician, not for use when drug is self-administered) Cardiology Pulmonary Arterial Hypertension EPOPROSTENOL (generic)
    [Show full text]
  • Deciphering Molecular Mechanisms and Prioritizing Therapeutic Targets in Cardio-Oncology
    Figure 1. This is a pilot view to explore the potential of EpiGraphDB to inform us about proteins that are linked to the pathophysiology of cancer and cardiovascular disease (CVD). For each cancer type (pink diamonds), we searched for cancer related proteins (light blue circles) that interact with other proteins identified as protein quantitative trait loci (pQTLs) for CVD (red diamonds for pathologies, orange triangles for risk factors). These pQTLs can be acting in cis (solid lines) or trans-acting (dotted lines). Proteins can interact either directly, a protein-protein interaction (dotted blue edges), or through the participation in the same pathway (red parallel lines). Shared pathways are represented with blue hexagons. We also queried which of these proteins are targeted by existing drugs. We found that the cancer drug cetuximab (yellow circle) inhibits EGFR. Other potential drugs are depicted in light brown hexagonal meta-nodes that are detailed below. Deciphering molecular mechanisms and prioritizing therapeutic targets in cardio-oncology Pau Erola1,2, Benjamin Elsworth1,2, Yi Liu2, Valeriia Haberland2 and Tom R Gaunt1,2,3 1 CRUK Integrative Cancer Epidemiology Programme; 2 MRC Integrative Epidemiology Unit, University of Bristol; 3 The Alan Turing Institute Cancer and cardiovascular disease (CVD) make by far the immense What is EpiGraphDB? contribution to the totality of human disease burden, and although mortality EpiGraphDB is an analytical platform and graph database that aims to is declining the number of those living with the disease shows little address the necessity of innovative and scalable approaches to harness evidence of change (Bhatnagar et al., Heart, 2016).
    [Show full text]
  • Therapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities
    REVIEW www.jasn.org Therapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities Chelsea C. Estrada,1 Alejandro Maldonado,1 and Sandeep K. Mallipattu1,2 1Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York; and 2Renal Section, Northport Veterans Affairs Medical Center, Northport, New York ABSTRACT Inhibition of vascular endothelial growth factor A (VEGFA)/vascular endothelial with hypertension and proteinuria. Re- growth factor receptor 2 (VEGFR2) signaling is a common therapeutic strategy in ports describe histologic changes in the oncology, with new drugs continuously in development. In this review, we consider kidney primarily as glomerular endothe- the experimental and clinical evidence behind the diverse nephrotoxicities associ- lial injury with thrombotic microangiop- ated with the inhibition of this pathway. We also review the renal effects of VEGF athy (TMA).8 Nephrotic syndrome has inhibition’s mediation of key downstream signaling pathways, specifically MAPK/ also been observed,9 with the clinical ERK1/2, endothelial nitric oxide synthase, and mammalian target of rapamycin manifestations varying according to (mTOR). Direct VEGFA inhibition via antibody binding or VEGF trap (a soluble decoy mechanism and direct target of VEGF receptor) is associated with renal-specific thrombotic microangiopathy (TMA). Re- inhibition. ports also indicate that tyrosine kinase inhibition of the VEGF receptors is prefer- Current VEGF inhibitors can be clas- entially associated with glomerulopathies such as minimal change disease and FSGS. sifiedbytheirtargetofactioninthe Inhibition of the downstream pathway RAF/MAPK/ERK has largely been associated VEGFA-VEGFR2 pathway: drugs that with tubulointerstitial injury. Inhibition of mTOR is most commonly associated with bind to VEGFA, sequester VEGFA, in- albuminuria and podocyte injury, but has also been linked to renal-specificTMA.In hibit receptor tyrosine kinases (RTKs), all, we review the experimentally validated mechanisms by which VEGFA-VEGFR2 or inhibit downstream pathways.
    [Show full text]
  • Leptomeningeal Metastases from Solid Tumors: Recent Advances in Diagnosis and Molecular Approaches
    cancers Review Leptomeningeal Metastases from Solid Tumors: Recent Advances in Diagnosis and Molecular Approaches Alessia Pellerino 1,* , Priscilla K. Brastianos 2, Roberta Rudà 1,3 and Riccardo Soffietti 1 1 Department of Neuro-Oncology, University and City of Health and Science Hospital, 10126 Turin, Italy; [email protected] (R.R.); riccardo.soffi[email protected] (R.S.) 2 Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02115, USA; [email protected] 3 Department of Neurology, Castelfranco Veneto and Brain Tumor Board Treviso Hospital, 31100 Treviso, Italy * Correspondence: [email protected]; Tel.: +39-011-633-4904 Simple Summary: Leptomeningeal metastases are a devastating complication of solid tumors with poor survival, regardless of the type of treatments. The limited efficacy of targeted agents is due to the molecular divergence between leptomeningeal recurrences and primary site, as well as the presence of a heterogeneous blood-brain barrier and blood-tumor barrier that interfere with the penetration of drugs into the brain. The diagnosis of leptomeningeal metastases is achieved by neurological examination, and/or brain and spinal magnetic resonance, and/or a positive cerebrospinal fluid cytology. The presence of neoplastic cells in the cerebrospinal fluid examination is the gold-standard for the diagnosis of leptomeningeal metastases; however, novel techniques known as “liquid biopsy” aim to improve the sensitivity and specificity in detecting circulating neoplastic cells or DNA in the cerebrospinal fluid. Targeted therapies and immunotherapies have changed the natural history Citation: Pellerino, A.; Brastianos, of metastatic solid tumors, including lung, breast cancer, and melanoma. Targeting actionable P.K.; Rudà, R.; Soffietti, R.
    [Show full text]
  • July 1, 2020 RE: Physician Administered Drugs (J Codes)
    July 1, 2020 RE: Physician Administered Drugs (J Codes) Included in Prior Authorization Matrix for Molina Healthcare of New York, Inc. Dear Participating Provider: Molina Healthcare of New York, Inc. requires prior authorization for these HCPCS codes for all participating providers. Prior authorization is required before services are rendered for the codes listed. Prior authorization requests should include the most up to date patient information including office notes, consultations, labs, scans, previous treatments tried, and any other patient specific information to support the request. Please fax a completed prior authorization form along with all supporting clinical documentation to fax number: 1-844- 823-5479. Our prior authorization form and most up to date formulary can be found on our website: MolinaHealthcare.com. C9061 INJECTION, TEPROTUMUMAB-TRBW, 10 mg C9063 INJECTION, EPTINEZUMAB-JJMR, 1 mg C9122 MOMETASONE FUROATE SINUS IMPLANT, 10 micrograms (sinuva) J0122 INJECTION, ERAVACYCLINE, 1 mg J0129 Injection, abatacept 10 mg J0178 Injection, aflibercept 1 mg J0179 INJECTION, BROLUCIZUMAB-DBLL, 1MG J0185 Injection, aprepitant 1 mg J0223 INJECTION, GIVOSIRAN, 0.5 mg J0285 INJECTION, AMPHOTERICIN B, 50 mg J0490 Injection, belimumab 10 mg J0517 Injection, benralizumab 1 mg J0567 Injection, cerliponase alfa 1 mg J0584 Injection, burosumab-twza 1 mg J0585 Injection, onabotulinumtoxina, 1 unit J0587 Injection, rimabotulinumtoxinb 100 units J0599 Injection, c-1 esterase inhibitor 10 units J0641 Injection, levoleucovorin, not otherwise
    [Show full text]
  • Cell-Cycle and DNA-Damage Response Pathway Is Involved In
    Published OnlineFirst October 13, 2017; DOI: 10.1158/1078-0432.CCR-17-1582 Biology of Human Tumors Clinical Cancer Research Cell-Cycle and DNA-Damage Response Pathway Is Involved in Leptomeningeal Metastasis of Non–Small Cell Lung Cancer Yun Fan1, Xuehua Zhu2, Yan Xu3, Xuesong Lu4, Yanjun Xu1, Mengzhao Wang3, Haiyan Xu4, Jingyan Ding2, Xin Ye2, Luo Fang5, Zhiyu Huang5, Lei Gong5, Hongyang Lu1, Weimin Mao1, and Min Hu2 Abstract Purpose: Leptomeningeal metastasis (LM) is a detrimental risk. Intriguingly, low overlapping of somatic protein-changing complication of non–small cell lung cancer (NSCLC) and asso- variants was observed between paired CSF and primary lesions, ciated with poor prognosis. However, the underlying mechanisms exhibiting tumor heterogeneity and genetic divergence. Moreover, of the metastasis process are still poorly understood. genes with CSF-recurrent genomic alterations were predominant- Experimental Design: We performed next-generation panel ly involved in cell-cycle regulation and DNA-damage response sequencing of primary tumor tissue, cerebrospinal fluid (CSF), (DDR), suggesting a role of the pathway in LM development. and matched normal controls from epidermal growth factor Conclusions: Our study has shed light on the genomic varia- receptor (EGFR) mutation-positive NSCLC patients with LM. tions of NSCLC-LM, demonstrated genetic heterogeneity and Results: The status of EGFR-activating mutations was highly divergence, uncovered involvement of cell-cycle and DDR path- concordant between primary tumor and CSF. PIK3CA aberrations way, and paved the way for potential therapeutic approaches to were high in these patients, implicating an association with LM this unmet medical need. Clin Cancer Res; 24(1); 209–16.
    [Show full text]
  • CDER Breakthrough Therapy Designation Approvals Data As of December 31, 2020 Total of 190 Approvals
    CDER Breakthrough Therapy Designation Approvals Data as of December 31, 2020 Total of 190 Approvals Submission Application Type and Proprietary Approval Use Number Number Name Established Name Applicant Date Treatment of patients with previously BLA 125486 ORIGINAL-1 GAZYVA OBINUTUZUMAB GENENTECH INC 01-Nov-2013 untreated chronic lymphocytic leukemia in combination with chlorambucil Treatment of patients with mantle cell NDA 205552 ORIGINAL-1 IMBRUVICA IBRUTINIB PHARMACYCLICS LLC 13-Nov-2013 lymphoma (MCL) Treatment of chronic hepatitis C NDA 204671 ORIGINAL-1 SOVALDI SOFOSBUVIR GILEAD SCIENCES INC 06-Dec-2013 infection Treatment of cystic fibrosis patients age VERTEX PHARMACEUTICALS NDA 203188 SUPPLEMENT-4 KALYDECO IVACAFTOR 21-Feb-2014 6 years and older who have mutations INC in the CFTR gene Treatment of previously untreated NOVARTIS patients with chronic lymphocytic BLA 125326 SUPPLEMENT-60 ARZERRA OFATUMUMAB PHARMACEUTICALS 17-Apr-2014 leukemia (CLL) for whom fludarabine- CORPORATION based therapy is considered inappropriate Treatment of patients with anaplastic NOVARTIS lymphoma kinase (ALK)-positive NDA 205755 ORIGINAL-1 ZYKADIA CERITINIB 29-Apr-2014 PHARMACEUTICALS CORP metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib Treatment of relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients NDA 206545 ORIGINAL-1 ZYDELIG IDELALISIB GILEAD SCIENCES INC 23-Jul-2014 for whom rituximab alone would be considered appropriate therapy due to other co-morbidities
    [Show full text]
  • Section 21 Ophthalmological Preparations Bevacizumab
    Section 21 Ophthalmological Preparations Bevacizumab - Addition Application submitted by International Council of Ophthalmology 1. Summary statement of the proposal for inclusion, change or deletion We propose the inclusion of bevacizumab, an angiogenesis inhibitor that is used off label in the treatment of proliferative (neovascular) eye diseases. Although bevacizumab was initially approved by the US FDA for the treatment of colorectal cancer, the visual acuity and anatomical results that were observed when bevacizumab was used to treat age-related macular degeneration (AMD) led to widespread use of off-label bevacizumab for the treatment of exudative AMD by 2006.1 It was also observed that the adverse side effects associated with intravenous bevacizumab administration appeared to be avoided with intravitreal administration of the drug.1 Since 2006, there have been reports of over fifty one ocular entities being treated with bevacizumab, generally those associated with neovascularization or vascular leakage as a consequence of an underlying disease.1 These include several types of choroidal neovascularization, retinal neovascularization, macular edema, neovascular glaucoma and radiation-induced eye diseases.1 Intravitreal bevacizumab administration is now used as a first line therapy for several diseases by many retina specialists and accounts for more than 50% of anti-VEGF administrations in the US.1 Additionally, the markedly lower cost of bevacizumab as compared to similarly effective drugs such as ranibizumab has led it its adoption for treatment of exudative AMD throughout the world.1 We therefore suggest that this drug be added to the WHO's existing list of essential eye medicines for use in developing countries. 2.
    [Show full text]
  • February 2021 EPS Pipeline Report
    Pipeline Report February 2021 Pipeline Report February 2021 © 2021 Envolve. All rights reserved. Page 1 This quarterly at-a-glance publication is developed by our Clinical Pharmacy Drug Information team to increase your understanding of the drug pipeline, Table of Contents ensuring you’re equipped with insights to prepare for shifts in pharmacy benefit management. In this issue, you’ll learn more about key themes and notable drugs referenced in the following points. COVID-19 1 > Veklury is currently the only agent that is FDA-approved for the treatment of COVID-19. Three additional therapeutics and two vaccines have been granted Emergency Use Authorization (EUA), and at least three more vaccines are Recent Specialty Drug Approvals1 4 expected to receive an EUA in the relatively near future. > The previous quarter noted the approval of several breakthrough therapies for rare or ultra-rare conditions, which previously had no available FDA-approved Recent Non-Specialty Drug Approvals 9 treatments — Zokinvy for Hutchinson-Gilford progeria syndrome and progeroid laminopathies, Oxlumo for primary hyperoxaluria type 1, and Imcivree for genetically mediated obesity. Upcoming Specialty Products 10 > Other notable approvals include: Lupkynis — the first oral therapy approved for lupus nephritis; Orladeyo — the first oral therapy approved as prophylaxis of hereditary angioedema attacks;Cabenuva – the first long-acting injectable antiretroviral therapy intended as maintenance treatment of HIV; and Breyanzi — Upcoming Non-Specialty Products 18 the
    [Show full text]
  • Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0192440 A1
    US 20190192440A1 (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0192440 A1 LI (43 ) Pub . Date : Jun . 27 , 2019 ( 54 ) ORAL DRUG DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF NANOPARTICLES (51 ) Int . CI. A61K 9 / 20 (2006 .01 ) ( 71 ) Applicant: Triastek , Inc. , Nanjing ( CN ) A61K 9 /00 ( 2006 . 01) A61K 31/ 192 ( 2006 .01 ) (72 ) Inventor : Xiaoling LI , Dublin , CA (US ) A61K 9 / 24 ( 2006 .01 ) ( 52 ) U . S . CI. ( 21 ) Appl. No. : 16 /289 ,499 CPC . .. .. A61K 9 /2031 (2013 . 01 ) ; A61K 9 /0065 ( 22 ) Filed : Feb . 28 , 2019 (2013 .01 ) ; A61K 9 / 209 ( 2013 .01 ) ; A61K 9 /2027 ( 2013 .01 ) ; A61K 31/ 192 ( 2013. 01 ) ; Related U . S . Application Data A61K 9 /2072 ( 2013 .01 ) (63 ) Continuation of application No. 16 /028 ,305 , filed on Jul. 5 , 2018 , now Pat . No . 10 , 258 ,575 , which is a (57 ) ABSTRACT continuation of application No . 15 / 173 ,596 , filed on The present disclosure provides a stable solid pharmaceuti Jun . 3 , 2016 . cal dosage form for oral administration . The dosage form (60 ) Provisional application No . 62 /313 ,092 , filed on Mar. includes a substrate that forms at least one compartment and 24 , 2016 , provisional application No . 62 / 296 , 087 , a drug content loaded into the compartment. The dosage filed on Feb . 17 , 2016 , provisional application No . form is so designed that the active pharmaceutical ingredient 62 / 170, 645 , filed on Jun . 3 , 2015 . of the drug content is released in a controlled manner. Patent Application Publication Jun . 27 , 2019 Sheet 1 of 20 US 2019 /0192440 A1 FIG .
    [Show full text]
  • Kadmon Holdings, Inc. Annual Report 2018
    Kadmon Holdings, Inc. Annual Report 2018 Form 10-K (NYSE:KDMN) Published: March 6th, 2018 PDF generated by stocklight.com ​ UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 _______________________________ FORM 10-K _______________________________ (Mark One) ☒ ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the fiscal year ended December 31, 2017 or ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For transition period from to . Commission File Number: 001-37841 Kadmon Holdings, Inc. (Exact name of registrant as specified in its charter) _______________________________ Delaware 27‑3576929 (State or other jurisdiction of (I.R.S. Employer incorporation or organization) Identification No.) 450 East 29th Street, New York, 10016 NY (Zip Code) (Address of principal executive offices) (212) 308‑6000 (Registrant’s telephone number, including area code) Securities registered pursuant to Section 12(b) of the Act: Title of each class Name of exchange on which registered Common Stock, par value $0.001 per share The New York Stock Exchange Securities registered pursuant to Section 12(g) of the Act: None _______________________________ Indicate by check mark if the Registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. YES ☐ NO ☒ Indicate by check mark if the Registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. YES ☐ NO ☒ Indicate by check mark whether the Registrant: (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the Registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days.
    [Show full text]
  • Management of Her2+ Brain and Leptomeningeal Disease
    Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. MANAGEMENT OF HER2+ BRAIN AND LEPTOMENINGEAL DISEASE Kathy D. Miller, M.D. Ballvé-Lantero Professor Indiana University Melvin and Bren Simon Cancer Center DISCLOSURES AbbVie Inc, Astellas Pharma Global Development Contracted Research Inc, Medivation Inc, a Pfizer Company, Merrimack Pharmaceuticals Inc, Novartis, Pfizer Inc Case presentation: Dr Brooks 69-year-old morbidly obese woman (350 pounds) with a history of DM • 2016: Metastatic ER/PR-negative, HER2- positive BC: 8-cm breast mass, 5-cm axillary mass, 3 liver lesions (9 cm, 7 cm and 2.5 cm) and 2 small lung lesions – Trastuzumab/pertuzumab/paclitaxel x 2 cycles • Mucositis, oral candida, diarrhea • Decreased paclitaxel dose - hypersensitivity reaction – Nab paclitaxel at 30% dose reduction à oral candida, umbilical candida, diarrhea, tachycardia – Currently on pertuzumab/trastuzumab and faring well Case presentation: Dr Hart 58-year-old woman • 2011: Metastatic ER/PR-positive, HER2- positive BC with symptomatic brain mets à surgical resection of brain lesion à XRT to brain à chemotherapy/trastuzumab à trastuzumab + AI • 2016: Lapatinib + capecitabine – Further resection of cerebellar lesions • 2017: Fulvestrant + lapatinib + capecitabine • Currently on fulvestrant + palbociclib + trastuzumab ROADMAP • Incidence • Guidelines for management • Systemic therapy • New directions BRAIN METASTASES IN BREAST CANCER Median Survival • Brain metastases ER-HER2+ 17.9 months common in breast TNBC 24% ER-HER2+ 31% ER+HER2+ 20.7 cancer months • Incidence and ER+HER2- 20% ER+HER2- 9.7 months outcome varies with ER+HER2+ 26% different breast TNBC cancer subtypes 6.4 months Brain Met Distribution n = 400 Sperduto, Int J Radiat Oncol Biol Phys.
    [Show full text]