DOCSLIB.ORG

CHMP Agenda of the 25-29 January 2021 Meeting

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
CHMP Agenda of the 25-29 January 2021 Meeting 26 January 2021 EMA/CHMP/47240/2021 Corr.11 Human Medicines Division Committee for medicinal products for human use (CHMP) Agenda for the meeting on 25-29 January 2021 Chair: Harald Enzmann – Vice-Chair: Bruno Sepodes 25 January 2021, 09:00 – 19:30, virtual meeting/ room 1C 26 January 2021, 08:30 – 19:30, virtual meeting/ room 1C 27 January 2021, 08:30 – 19:30, virtual meeting/ room 1C 28 January 2021, 08:30 – 19:30, virtual meeting/ room 1C 29 January 2021, 08:30 – 18:00, virtual meeting/ room 1C Disclaimers Some of the information contained in this agenda is considered commercially confidential or sensitive and therefore not disclosed. With regard to intended therapeutic indications or procedure scopes listed against products, it must be noted that these may not reflect the full wording proposed by applicants and may also vary during the course of the review. Additional details on some of these procedures will be published in the CHMP meeting highlights once the procedures are finalised and start of referrals will also be available. Of note, this agenda is a working document primarily designed for CHMP members and the work the Committee undertakes. Note on access to documents Some documents mentioned in the agenda cannot be released at present following a request for access to documents within the framework of Regulation (EC) No 1049/2001 as they are subject to on- going procedures for which a final decision has not yet been adopted. They will become public when adopted or considered public according to the principles stated in the Agency policy on access to documents (EMA/127362/2006). 1 Correction in section 9.1.5 Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2020. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Introduction 8 1.1. Welcome and declarations of interest of members, alternates and experts ............ 8 1.2. Adoption of agenda ................................................................................................ 8 1.3. Adoption of the minutes ......................................................................................... 8 2. Oral Explanations 8 2.1. Pre-authorisation procedure oral explanations ....................................................... 8 2.1.1. salmeterol xinafoate / fluticasone propionate - EMEA/H/C/005591 ................................... 8 2.1.2. salmeterol xinafoate / fluticasone propionate - EMEA/H/C/004881 ................................... 8 2.1.3. COVID-19 Vaccine (ChAdOx1-S [recombinant]) – EMEA/H/C/005675 ............................... 9 2.2. Re-examination procedure oral explanations ......................................................... 9 2.3. Post-authorisation procedure oral explanations ..................................................... 9 2.3.1. Epidyolex - cannabidiol - Orphan - EMEA/H/C/004675/II/0005 ........................................ 9 2.3.2. Trelegy Ellipta - fluticasone furoate / umeclidinium / vilanterol - EMEA/H/C/004363/X/0012/G ............................................................................................................................... 9 2.4. Referral procedure oral explanations ................................................................... 10 3. Initial applications 10 3.1. Initial applications; Opinions ................................................................................ 10 3.1.1. bevacizumab - EMEA/H/C/005286 ............................................................................. 10 3.1.2. salmeterol xinafoate / fluticasone propionate - EMEA/H/C/005591 ................................. 10 3.1.3. remimazolam - EMEA/H/C/005246 ............................................................................. 10 3.1.4. dostarlimab - EMEA/H/C/005204 ............................................................................... 11 3.1.5. ofatumumab - EMEA/H/C/005410 .............................................................................. 11 3.1.6. selinexor - Orphan - EMEA/H/C/005127 ..................................................................... 11 3.1.7. cenobamate - EMEA/H/C/005377 .............................................................................. 11 3.1.8. bevacizumab - EMEA/H/C/005556 ............................................................................. 11 3.1.9. pemigatinib - Orphan - EMEA/H/C/005266 .................................................................. 12 3.1.10. salmeterol xinafoate / fluticasone propionate - EMEA/H/C/004881 ................................. 12 3.1.11. somapacitan - Orphan - EMEA/H/C/005030 ................................................................ 12 3.1.12. thiotepa - EMEA/H/C/005434 .................................................................................... 12 3.1.13. icosapent ethyl - EMEA/H/C/005398 .......................................................................... 13 3.1.14. COVID-19 Vaccine (ChAdOx1-S [recombinant]) – EMEA/H/C/005675 ............................. 13 3.1.15. Comirnaty - COVID-19 mRNA vaccine (nucleoside-modified) - EMEA/H/C/005735 ........... 13 3.1.16. COVID-19 Vaccine Moderna – COVID-19 mRNA vaccine (nucleoside-modified) - EMEA/H/C/005791 ................................................................................................... 13 3.2. Initial applications; List of outstanding issues (Day 180; Day 120 for procedures with accelerated assessment timetable) ...................................................................... 14 Committee for medicinal products for human use (CHMP) EMA/CHMP/47240/2021 Page 2/41 3.2.1. abiraterone acetate - EMEA/H/C/005408 .................................................................... 14 3.2.2. hydrocortisone - Orphan - EMEA/H/C/005105 ............................................................. 14 3.2.3. estetrol / drospirenone - EMEA/H/C/005336................................................................ 14 3.2.4. risdiplam - Orphan - EMEA/H/C/005145 ..................................................................... 14 3.2.5. pralsetinib - EMEA/H/C/005413 ................................................................................. 14 3.2.6. estetrol / drospirenone - EMEA/H/C/005382................................................................ 15 3.2.7. ponesimod - EMEA/H/C/005163 ................................................................................ 15 3.2.8. tanezumab - EMEA/H/C/005189 ................................................................................ 15 3.2.9. relugolix / estradiol / norethisterone acetate - EMEA/H/C/005267 .................................. 15 3.3. Initial applications; List of questions (Day 120; Day 90 for procedures with accelerated assessment timetable) ...................................................................... 15 3.3.1. abrocitinib - EMEA/H/C/005452 ................................................................................. 15 3.3.2. artesunate - Orphan - EMEA/H/C/005550 ................................................................... 16 3.3.3. avalglucosidase alfa - Orphan - EMEA/H/C/005501 ...................................................... 16 3.3.4. ranibizumab - EMEA/H/C/005545 .............................................................................. 16 3.3.5. lonapegsomatropin - Orphan - EMEA/H/C/005367 ....................................................... 16 3.3.6. adalimumab - EMEA/H/C/005548 .............................................................................. 16 3.3.7. teriparatide - EMEA/H/C/004932 ............................................................................... 16 3.3.8. pegcetacoplan - Orphan - EMEA/H/C/005553 .............................................................. 16 3.3.9. ripretinib - Orphan - EMEA/H/C/005614 ..................................................................... 17 3.3.10. rivaroxaban - EMEA/H/C/005600 ............................................................................... 17 3.3.11. autologous glioma tumor cells, inactivated / autologous glioma tumor cell lysates, inactivated / allogeneic glioma tumor cells, inactivated / allogeneic glioma tumor cell lysates, inactivated - Orphan - ATMP - EMEA/H/C/003693 .......................................................................... 17 3.3.12. elivaldogene autotemcel - Orphan - ATMP - EMEA/H/C/003690 ..................................... 17 3.4. Update on on-going initial applications for Centralised procedure ........................ 17 3.4.1. zanubrutinib - Orphan - EMEA/H/C/004978 ................................................................. 17 3.4.2. leuprorelin - EMEA/H/C/005034 ................................................................................. 18 3.4.3. doxorubicin hydrochloride - EMEA/H/C/005330 ........................................................... 18 3.4.4. doxorubicin - EMEA/H/C/005320 ............................................................................... 18 3.4.5. sildenafil - EMEA/H/C/005439 ................................................................................... 18 3.4.6. sitagliptin - EMEA/H/C/005598 .................................................................................. 19 3.4.7. trastuzumab - EMEA/H/C/005066 .............................................................................
Load more

Recommended publications
  • XTANDI® (Enzalutamide): a Treatment Option for Castration-Resistant Prostate Cancer (CRPC)
    XTANDI® (enzalutamide): A Treatment Option for Castration-Resistant Prostate Cancer (CRPC) XTANDI® (enzalutamide) is approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with castration-resistant prostate cancer (CRPC).1 XTANDI is the first and only oral medication FDA-approved for both non-metastatic and metastatic CRPC.1 ABOUT THE ASTELLAS/PFIZER HOW XTANDI WORKS COLLABORATION Astellas and Pfizer jointly XTANDI is indicated for the treatment of CRPC, commercialize XTANDI which is defined as disease progression on in the United States. androgen deprivation therapy (luteinizing hormone-releasing hormone (LHRH) therapy Astellas has responsibility or prior bilateral orchiectomy).2 for manufacturing and all additional regulatory In prostate cancer, the androgen receptor (AR) is a key driver filings globally, as well as of progression.3 XTANDI is an AR inhibitor that is thought commercializing XTANDI to act on multiple steps of the androgen receptor signaling 1 outside the United States. pathway within the tumor cell based on in vitro studies. Select Safety Information Seizure occurred in 0.4% of patients receiving XTANDI in clinical studies. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. Patients in the study had one or more of the following pre-disposing factors: use of medications that may lower the seizure threshold; history of traumatic brain or head injury, cerebrovascular accident or transient ischemic attack, Alzheimer’s disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, history of seizure, presence of a space occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection.
    [Show full text]
  • Stanford Chem-H Presentation (PDF)
    KiNativ® In situ kinase profiling Stanford University ChEM-H confidential @KiNativPlatform Principle of the KiNativ platform • ATP (or ADP) acyl phosphate binds to, and covalently modifies Lysine residues in the active site • Thus, ATP acyl phosphate with a desthiobiotin tag can be used capture and quantitate kinases in a complex lysate Acyl phosphate Desthiobiotin tag ATP 2 ATP acyl phosphate probe covalently modifies kinase in the active site Lysine 2 Lysine 1 3 ATP acyl phosphate probe covalently modifies kinase in the active site Lysine 2 Lysine 1 4 Samples trypsinized, probe-labeled peptides captured with streptavidin, and analyzed by targeted LC-MS2 Identification Quantitation Explicit determination of peptide Integration of signal from MS2 sequence and probe modification site fragment ions from MS2 spectrum 5 Comprehensive Coverage of Protein and Lipid Kinases Protein kinases Atypical kinases Green: Kinases detected on KiNativ Red: Kinases not detected on KiNativ ~80% of known protein and atypical kinases identified on the platform http://www.kinativ.com/coverage/protein-lipid.html 6 Profiling compound(s) on the KiNativ platform Control sample – add probe Sample: Lysate derived from any cell line or tissue from ANY species Treated sample – add inhibitor followed by probe Inhibited kinase Green: Kinases Blue: Probe Gray: Non-kinases Red: Inhibitor 7 Profiling compound(s) on the KiNativ platform Control sample – add probe MS signalMS Sample: Lysate derived from any cell line or tissue from ANY species Treated sample – add inhibitor
    [Show full text]
  • LHRH) Antagonist Cetrorelix and LHRH Agonist Triptorelin on the Gene Expression of Pituitary LHRH Receptors in Rats
    Comparison of mechanisms of action of luteinizing hormone-releasing hormone (LHRH) antagonist cetrorelix and LHRH agonist triptorelin on the gene expression of pituitary LHRH receptors in rats Magdolna Kovacs*†‡ and Andrew V. Schally*†§ *Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, New Orleans, LA 70112; and †Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112 Contributed by Andrew V. Schally, August 21, 2001 The mechanisms through which luteinizing hormone (LH)-releasing however, are different. LHRH agonists achieve the inhibition of hormone (LHRH) antagonists suppress pituitary gonadotroph func- gonadotropin secretion after a period of continuous exposure (1, tions and LHRH-receptor (LHRH-R) expression are incompletely un- 2, 11–14). In contrast, antagonists of LHRH produce a compet- derstood. Consequently, we investigated the direct effect of LHRH itive blockade of LHRH-R and cause an immediate cessation of antagonist cetrorelix in vitro on the expression of the pituitary the release of gonadotropins and sex steroids, reducing the time LHRH-R gene and its ability to counteract the exogenous LHRH and of the onset of therapeutic effects as compared with the agonists the agonist triptorelin in the regulation of this gene. We also com- (1, 2, 15–17). LHRH agonists such as triptorelin, leuprolide, pared the effects of chronic administration of cetrorelix and triptore- buserelin, or goserelin (1, 2, 14) have been used worldwide for lin on the LHRH-R mRNA level and gonadotropin secretion in ovari- nearly two decades, but LHRH antagonists such as cetrorelix, ectomized (OVX) and normal female rats. The exposure of pituitary ganirelix, and Abarelix have been introduced into the clinical cells in vitro to 3-min pulses of 1 nM LHRH or 0.1 nM triptorelin for 5 h practice relatively recently (1, 2, 15, 16).
    [Show full text]
  • AHFS Pharmacologic-Therapeutic Classification System
    AHFS Pharmacologic-Therapeutic Classification System Abacavir 48:24 - Mucolytic Agents - 382638 8:18.08.20 - HIV Nucleoside and Nucleotide Reverse Acitretin 84:92 - Skin and Mucous Membrane Agents, Abaloparatide 68:24.08 - Parathyroid Agents - 317036 Aclidinium Abatacept 12:08.08 - Antimuscarinics/Antispasmodics - 313022 92:36 - Disease-modifying Antirheumatic Drugs - Acrivastine 92:20 - Immunomodulatory Agents - 306003 4:08 - Second Generation Antihistamines - 394040 Abciximab 48:04.08 - Second Generation Antihistamines - 394040 20:12.18 - Platelet-aggregation Inhibitors - 395014 Acyclovir Abemaciclib 8:18.32 - Nucleosides and Nucleotides - 381045 10:00 - Antineoplastic Agents - 317058 84:04.06 - Antivirals - 381036 Abiraterone Adalimumab; -adaz 10:00 - Antineoplastic Agents - 311027 92:36 - Disease-modifying Antirheumatic Drugs - AbobotulinumtoxinA 56:92 - GI Drugs, Miscellaneous - 302046 92:20 - Immunomodulatory Agents - 302046 92:92 - Other Miscellaneous Therapeutic Agents - 12:20.92 - Skeletal Muscle Relaxants, Miscellaneous - Adapalene 84:92 - Skin and Mucous Membrane Agents, Acalabrutinib 10:00 - Antineoplastic Agents - 317059 Adefovir Acamprosate 8:18.32 - Nucleosides and Nucleotides - 302036 28:92 - Central Nervous System Agents, Adenosine 24:04.04.24 - Class IV Antiarrhythmics - 304010 Acarbose Adenovirus Vaccine Live Oral 68:20.02 - alpha-Glucosidase Inhibitors - 396015 80:12 - Vaccines - 315016 Acebutolol Ado-Trastuzumab 24:24 - beta-Adrenergic Blocking Agents - 387003 10:00 - Antineoplastic Agents - 313041 12:16.08.08 - Selective
    [Show full text]
  • JAK Inhibitors for Treatment of Psoriasis: Focus on Selective TYK2 Inhibitors
    Drugs https://doi.org/10.1007/s40265-020-01261-8 CURRENT OPINION JAK Inhibitors for Treatment of Psoriasis: Focus on Selective TYK2 Inhibitors Miguel Nogueira1 · Luis Puig2 · Tiago Torres1,3 © Springer Nature Switzerland AG 2020 Abstract Despite advances in the treatment of psoriasis, there is an unmet need for efective and safe oral treatments. The Janus Kinase– Signal Transducer and Activator of Transcription (JAK–STAT) pathway plays a signifcant role in intracellular signalling of cytokines of numerous cellular processes, important in both normal and pathological states of immune-mediated infamma- tory diseases. Particularly in psoriasis, where the interleukin (IL)-23/IL-17 axis is currently considered the crucial pathogenic pathway, blocking the JAK–STAT pathway with small molecules would be expected to be clinically efective. However, relative non-specifcity and low therapeutic index of the available JAK inhibitors have delayed their integration into the therapeutic armamentarium of psoriasis. Current research appears to be focused on Tyrosine kinase 2 (TYK2), the frst described member of the JAK family. Data from the Phase II trial of BMS-986165—a selective TYK2 inhibitor—in psoriasis have been published and clinical results are encouraging, with a large Phase III programme ongoing. Further, the selective TYK2 inhibitor PF-06826647 is being tested in moderate-to-severe psoriasis in a Phase II clinical trial. Brepocitinib, a potent TYK2/JAK1 inhibitor, is also being evaluated, as both oral and topical treatment. Results of studies with TYK2 inhibitors will be important in assessing the clinical efcacy and safety of these drugs and their place in the therapeutic armamentarium of psoriasis.
    [Show full text]
  • Phase I/II Study Evaluating the Safety and Clinical Efficacy of Temsirolimus and Bevacizumab in Patients with Chemotherapy Refra
    Investigational New Drugs (2019) 37:331–337 https://doi.org/10.1007/s10637-018-0687-5 PHASE II STUDIES Phase I/II study evaluating the safety and clinical efficacy of temsirolimus and bevacizumab in patients with chemotherapy refractory metastatic castration-resistant prostate cancer Pedro C. Barata1 & Matthew Cooney2 & Prateek Mendiratta 2 & Ruby Gupta3 & Robert Dreicer4 & Jorge A. Garcia3 Received: 25 September 2018 /Accepted: 16 October 2018 /Published online: 7 November 2018 # Springer Science+Business Media, LLC, part of Springer Nature 2018 Summary Background Mammalian target of rapamycin (mTOR) pathway and angiogenesis through vascular endothelial growth factor (VEGF) have been shown to play important roles in prostate cancer progression. Preclinical data in prostate cancer has suggested the potential additive effect dual inhibition of VEGF and mTOR pathways. In this phase I/II trial we assessed the safety and efficacy of bevacizumab in combination with temsirolimus for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC). Methods In the phase I portion, eligible patients received temsirolimus (20 mg or 25 mg IV weekly) in combination with a fixed dose of IV bevacizumab (10 mg/kg every 2 weeks). The primary endpoint for the phase II portion was objective response measured by either PSA or RECIST criteria. Exploratory endpoints included changes in circulating tumor cells (CTC) and their correlation with PSA response to treatment. Results Twenty-one patients, median age 64 (53–82), with pre- treatment PSA of 205.3 (11.1–1801.0), previously treated with a median of 2 (0–5) lines of therapy for mCRPC received the combination of temsirolimus weekly at 20 mg (n =4)or25mg(n = 17) with bevacizumab 10 mg/kg every 2 weeks (n =21).
    [Show full text]
  • Australian Public Assessment for Efmoroctocog Alfa (Rhu)
    Australian Public Assessment Report 1 for efmoroctocog alfa (rhu) Proprietary Product Name: Eloctate Sponsor: Biogen Idec Australia Pty Ltd January 2015 1 The non-proprietary name has changed post registration from efraloctocog alfa to efmoroctocog afla to harmonise with the International Non-proprietary Name. Therapeutic Goods Administration About the Therapeutic Goods Administration (TGA) · The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health and is responsible for regulating medicines and medical devices. · The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary. · The work of the TGA is based on applying scientific and clinical expertise to decision- making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. · The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action. · To report a problem with a medicine or medical device, please see the information on the TGA website <http://www.tga.gov.au>. About AusPARs · An Australian Public Assessment Record (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission. · AusPARs are prepared and published by the TGA. · An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations, and extensions of indications. · An AusPAR is a static document, in that it will provide information that relates to a submission at a particular point in time.
    [Show full text]
  • (CHMP) Agenda for the Meeting on 22-25 February 2021 Chair: Harald Enzmann – Vice-Chair: Bruno Sepodes
    22 February 2021 EMA/CHMP/107904/2021 Human Medicines Division Committee for medicinal products for human use (CHMP) Agenda for the meeting on 22-25 February 2021 Chair: Harald Enzmann – Vice-Chair: Bruno Sepodes 22 February 2021, 09:00 – 19:30, room 1C 23 February 2021, 08:30 – 19:30, room 1C 24 February 2021, 08:30 – 19:30, room 1C 25 February 2021, 08:30 – 19:30, room 1C Disclaimers Some of the information contained in this agenda is considered commercially confidential or sensitive and therefore not disclosed. With regard to intended therapeutic indications or procedure scopes listed against products, it must be noted that these may not reflect the full wording proposed by applicants and may also vary during the course of the review. Additional details on some of these procedures will be published in the CHMP meeting highlights once the procedures are finalised and start of referrals will also be available. Of note, this agenda is a working document primarily designed for CHMP members and the work the Committee undertakes. Note on access to documents Some documents mentioned in the agenda cannot be released at present following a request for access to documents within the framework of Regulation (EC) No 1049/2001 as they are subject to on- going procedures for which a final decision has not yet been adopted. They will become public when adopted or considered public according to the principles stated in the Agency policy on access to documents (EMA/127362/2006). Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2021.
    [Show full text]
  • Actemra® (Tocilizumab)
    Actemra® (tocilizumab) (Intravenous) Document Number: MODA-0002 Last Review Date: 10/26/2020 Date of Origin: 09/21/2010 Dates Reviewed: 12/2010, 03/2011, 05/2011, 06/2011, 09/2011, 12/2011, 03/2012, 06/2012, 09/2012, 09/2012, 11/2012, 12/2012, 03/2013, 06/2013, 09/2013, 11/2013, 12/2013, 03/2014, 06/2014, 09/2014, 12/2014, 03/2015, 05/2015, 09/2015, 12/0215, 03/2016, 06/2016, 09/2016, 12/2016, 03/2017, 05/2017, 09/2017, 12/2017, 03/2018, 06/2018, 10/2018, 10/2019, 10/2020, 11/2020 I. Length of Authorization Coverage will be provided as follows: o Castleman’s Disease: 4 months and may be renewed o Cytokine Release Syndrome: 4 doses only and may not be renewed o Immune Checkpoint Inhibitor related arthritis: 1 dose and may not be renewed o All other indications: 6 months and may be renewed. II. Dosing Limits A. Quantity Limit (max daily dose) [NDC Unit]: o Actemra 80 mg/4 mL vial: 1 vial per 14 days o Actemra 200 mg/10 mL vial: 1 vial per 14 days o Actemra 400 mg/20 mL vial: 2 vials per 14 days B. Max Units (per dose and over time) [HCPCS Unit]: Diagnosis Billable Units Interval (days) Rheumatoid Arthritis & Polyarticular Juvenile Idiopathic 800 28 Arthritis, NMOSD Systemic Juvenile Idiopathic Arthritis, Castleman’s Disease (NHL) & Acute Graft Versus Host Disease 800 14 (aGVHD) Cytokine Release Syndrome (CRS) 3200 1 course of therapy only Immune Checkpoint Inhibitor related arthritis 800 1 course of therapy only III.
    [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]
  • Antibody–Drug Conjugates
    Published OnlineFirst April 12, 2019; DOI: 10.1158/1078-0432.CCR-19-0272 Review Clinical Cancer Research Antibody–Drug Conjugates: Future Directions in Clinical and Translational Strategies to Improve the Therapeutic Index Steven Coats1, Marna Williams1, Benjamin Kebble1, Rakesh Dixit1, Leo Tseng1, Nai-Shun Yao1, David A. Tice1, and Jean-Charles Soria1,2 Abstract Since the first approval of gemtuzumab ozogamicin nism of activity of the cytotoxic warhead. However, the (Mylotarg; Pfizer; CD33 targeted), two additional antibody– enthusiasm to develop ADCs has not been dampened; drug conjugates (ADC), brentuximab vedotin (Adcetris; Seat- approximately 80 ADCs are in clinical development in tle Genetics, Inc.; CD30 targeted) and inotuzumab ozogami- nearly 600 clinical trials, and 2 to 3 novel ADCs are likely cin (Besponsa; Pfizer; CD22 targeted), have been approved for to be approved within the next few years. While the hematologic cancers and 1 ADC, trastuzumab emtansine promise of a more targeted chemotherapy with less tox- (Kadcyla; Genentech; HER2 targeted), has been approved to icity has not yet been realized with ADCs, improvements treat breast cancer. Despite a clear clinical benefit being dem- in technology combined with a wealth of clinical data are onstrated for all 4 approved ADCs, the toxicity profiles are helping to shape the future development of ADCs. In this comparable with those of standard-of-care chemotherapeu- review, we discuss the clinical and translational strategies tics, with dose-limiting toxicities associated with the mecha- associated with improving the therapeutic index for ADCs. Introduction in antibody, linker, and warhead technologies in significant depth (2, 3, 8, 9). Antibody–drug conjugates (ADC) were initially designed to leverage the exquisite specificity of antibodies to deliver targeted potent chemotherapeutic agents with the intention of improving Overview of ADCs in Clinical Development the therapeutic index (the ratio between the toxic dose and the Four ADCs have been approved over the last 20 years (Fig.
    [Show full text]
  • SGO-2020-Annual-Meet
    Society of Gynecologic Oncology 2020 Annual Meeting on Women’s Cancer Abstracts for Oral Presentation Scientific Plenary I: Shaping the Future with Innovative Clinical Trials: A Clearer Vision Ahead in Gynecologic Cancer 1 - Scientific Plenary Sentinel lymph node biopsy versus lymphadenectomy for high-grade endometrial cancer staging (SENTOR trial): A prospective multicenter cohort study M.C. Cusimanoa, D. Vicusb, K. Pulmanc, M.Q. Bernardinid, S. Laframboised, T. Mayd, G. Bouchard-Fortierd, L. Hogend, L.T. Gienb, A.L. Covensb, R. Kupetse, B.A. Clarkea, M. Cesaric, M. Rouzbahmand, J. Mirkovicb, G. Turashvilid, M. Magantid, A. Ziad, G.E.V. Ened and S.E. Fergusond. aUniversity of Toronto, Toronto, ON, Canada, bSunnybrook Odette Cancer Centre, Toronto, ON, Canada, cTrillium Health Partners, Credit Valley Hospital/University of Toronto, Mississauga, ON, Canada, dPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, eSunnybrook Cancer Centre/University of Toronto, Toronto, ON, Canada Objective: It is unclear whether sentinel lymph node biopsy (SLNB) can replace complete lymphadenectomy in women with high-grade endometrial cancer (EC). We performed a prospective multicenter cohort study (the SENTOR trial) to evaluate the performance characteristics of SLNB using indocyanine green (ICG) in stage I high-grade EC (ClinicalTrials.gov ID: NCT01886066). Method: Patients with clinical stage I grade 2 endometrioid or high-grade EC (grade 3 endometrioid, serous, clear cell, carcinosarcoma, undifferentiated, or mixed tumors) undergoing laparoscopic or robotic surgery at 3 cancer centers in Toronto, Canada, were prospectively recruited for SLNB with ICG. After SLNB, high-grade EC patients underwent pelvic and paraaortic lymphadenectomy (PLND/PALND), and grade 2 endometrioid EC patients underwent PLND only.
    [Show full text]