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Pros and Cons of Entry and Fusion Inhibitors (Review)
MOLECULAR MEDICINE REPORTS 19: 1987-1995, 2019 Investigational drugs in HIV: Pros and cons of entry and fusion inhibitors (Review) EMMANUELE VENANZI RULLO1,2, MANUELA CECCARELLI1, FABRIZIO CONDORELLI3, ALESSIO FACCIOLÀ1, GIUSEPPA VISALLI4, FRANCESCO D'ALEO1, IVANA PAOLUCCI1, BRUNO CACOPARDO5, MARILIA RITA PINZONE2-5, MICHELE DI ROSA6, GIUSEPPE NUNNARI1 and GIOVANNI F. PELLICANÒ7 1Department of Clinical and Experimental Medicine, Unit of Infectious Diseases, University of Messina, I-90124 Messina, Italy; 2Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; 3Department of Pharmacological Sciences, University of Eastern Piedmont ‘A. Avogadro’, I-13100 Novara; 4Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, I-90124 Messina; 5Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania; 6Department of Biomedical and Biotechnological Sciences, Human Anatomy and Histology Section, University of Catania, I-95123 Catania; 7Department of Human Pathology of the Adult and the Developmental Age ‘G. Barresi’, Unit of Infectious Diseases, University of Messina, I-98122 Messina, Italy Received September 2, 2018; Accepted November 29, 2018 DOI: 10.3892/mmr.2019.9840 Abstract. Despite the profound changes and improve- 4. Gp41 antagonists ments reached in the field of HIV treatment, tolerability and 5. CD4 antagonists adherence to highly active antiretroviral therapy remains a 6. Discussion challenge. Furthermore, multi-experienced patients could take advantage of drugs with different mechanisms of action to combat the spread of resistance to actual therapy. For these 1. Introduction reasons identification of new HIV drugs is crucial. Among all the molecules that at present are under investigation, entry HIV continues to be an important challenge and a major and fusion inhibitors pose an interesting class owing to their global public health issue. -
Pharmacologic Considerations in the Disposition of Antibodies and Antibody-Drug Conjugates in Preclinical Models and in Patients
antibodies Review Pharmacologic Considerations in the Disposition of Antibodies and Antibody-Drug Conjugates in Preclinical Models and in Patients Andrew T. Lucas 1,2,3,*, Ryan Robinson 3, Allison N. Schorzman 2, Joseph A. Piscitelli 1, Juan F. Razo 1 and William C. Zamboni 1,2,3 1 University of North Carolina (UNC), Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA; [email protected] (J.A.P.); [email protected] (J.F.R.); [email protected] (W.C.Z.) 2 Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; [email protected] 3 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-919-966-5242; Fax: +1-919-966-5863 Received: 30 November 2018; Accepted: 22 December 2018; Published: 1 January 2019 Abstract: The rapid advancement in the development of therapeutic proteins, including monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs), has created a novel mechanism to selectively deliver highly potent cytotoxic agents in the treatment of cancer. These agents provide numerous benefits compared to traditional small molecule drugs, though their clinical use still requires optimization. The pharmacology of mAbs/ADCs is complex and because ADCs are comprised of multiple components, individual agent characteristics and patient variables can affect their disposition. To further improve the clinical use and rational development of these agents, it is imperative to comprehend the complex mechanisms employed by antibody-based agents in traversing numerous biological barriers and how agent/patient factors affect tumor delivery, toxicities, efficacy, and ultimately, biodistribution. -
Keeping up with FDA Drug Approvals: 60 New Drugs in 60 Minutes Elizabeth A
Keeping Up with FDA Drug Approvals: 60 New Drugs in 60 Minutes Elizabeth A. Shlom, PharmD, BCPS Senior Vice President & Director Clinical Pharmacy Program | Acurity, Inc. Privileged and Confidential April 10, 2019 Privileged and Confidential Program Objectives By the end of the presentation, the pharmacist or pharmacy technician participant will be able to: ▪ Identify orphan drugs and first-in-class medications approved by the FDA in 2018. ▪ List five new drugs and their indications. ▪ Identify the place in therapy for three novel monoclonal antibodies. ▪ Discuss at least two new medications that address public health concerns. Dr. Shlom does not have any conflicts of interest in regard to this presentation. Both trade names and generic names will be discussed throughout the presentation Privileged and Confidential 2018 NDA Approvals (NMEs/BLAs) ▪ Lutathera (lutetium Lu 177 dotatate) ▪ Braftovi (encorafenib) ▪ Vizimpro (dacomitinib) ▪ Biktarvy (bictegravir, emtricitabine, ▪ TPOXX (tecovirimat) ▪ Libtayo (cemiplimab-rwic) tenofovir, ▪ Tibsovo (ivosidenib) ▪ Seysara (sarecycline) alafenamide) ▪ Krintafel (tafenoquine) ▪ Nuzyra (omadacycline) ▪ Symdeko (tezacaftor, ivacaftor) ▪ Orilissa (elagolix sodium) ▪ Revcovi (elapegademase-lvir) ▪ Erleada (apalutamide) ▪ Omegaven (fish oil triglycerides) ▪ Tegsedi (inotersen) ▪ Trogarzo (ibalizumab-uiyk) ▪ Mulpleta (lusutrombopag) ▪ Talzenna (talazoparib) ▪ Ilumya (tildrakizumab-asmn) ▪ Poteligeo (mogamulizumab-kpkc) ▪ Xofluza (baloxavir marboxil) ▪ Tavalisse (fostamatinib disodium) ▪ Onpattro (patisiran) -
HPTN 083 – Injectable Cabotegravir (CAB) for Prep
CROI 2021 Update: Evaluating Options for Long-Acting PreP 4/15/2021 Nicholas Yared, M.D. Infectious Disease Senior Staff Henry Ford Health System HPTN 083 – Injectable Cabotegravir (CAB) for PrEP • HPTN 083 showed 66% reduction in HIV incidence in men who have sex with men (MSM) and transgender women (TGW) randomized to CAB 600mg every 8 weeks vs. daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) • 58 incident infections among 4566 participants • 13 in CAB group, annual incidence 0.41% • 39 in TDF/FTC group, annual incidence 1.22% • Marzinke et al. used data from HPTN 083 to characterize the 58 cases where infection occurred Marzinke M, et al. Laboratory analysis of HIV infections in HPTN 083: Injectable CAB for PrEP Lab Analysis of HPTN 083 – Methods • Plasma concentrations of CAB and TFV-diphosphate • Concentrations from dried blood spots (DBS) using liquid chromatography-tandem mass spectrometry • HIV Ag/Ab test, HIV discriminatory test, and RNA assays for HIV status and timing • Resistance testing to look for resistance-associated mutations (RAMs) if HIV-1 RNA level > 500 copies/mL Marzinke M, et al. Laboratory analysis of HIV infections in HPTN 083: Injectable CAB for PrEP Results of Lab Analysis of Incident HIV Cases in HPTN 083 – Cabotegravir Arm • 12 incident infections • 5 with no recent CAB dosing • 4 occurred despite on-time CAB injections & targeted CAB concentrations • 3 occurred in oral lead-in phase (1 had no CAB detected) • RAMs • 5 had INSTI-related mutations (Q148 or R263K) • 1 had NNRTI mutations only • 1 had NRTI & NNRTI mutations Marzinke M, et al. -
An HIV Clinician's View
HIV Meets Oncology: An HIV Clinician’s View Merceditas S. Villanueva MD Director, HIV/AIDS Program Yale University School of Medicine HIV and Cancer Retreat April 30, 2019 Financial Disclosures • None Case Presentation • 58 year old man diagnosed with HIV in 1996 • Early years: serial ART mono and dual therapy with multidrug resistance • Moved to CT 2005-worked in pharmaceutical field (ART development) • I met him in 2009-applying for disability ART Over Time Saquinavir Tenofovir Emtricitabine Stavudine Ritonavir Atazanavir Maraviroc Elvitegravir Zidovudine Doravirine Indinavir Enfuvirtide Raltegravir Nelfinavir Ibalizumab 1985 1990 1995 2000 2005 2010 2015 2018 Didanosine Tenofovir Lamivudine Efavirenz Darunavir Rilpivirine alafenamide Abacavir Fosemprenavir Dolutegravir Nevirapine Lopinavir+Ritonavir Etravirine ART in Single Tablet Regimen Now 1 pill a Day 2-3 ARVs co-formulated ART Simpler and Safer AN AIDS TIMELINE: The 1st Decade RONALD REAGAN GEORGE H.W. BUSH 1981-1989 1989-1993 ’85 ’87 AZT ’82 First approved HIV “AIDS” ’83 Virus test isolation 1981 AN AIDS TIMELINE: The 2nd Decade GEORGE H.W. BUSH WILLIAM CLINTON 1989-1993 1993-2000 92’ ddl/ddC 93’ d4t Dual NRTI’s HAART ’97: NEL, DLV, Combivir ’95: Saquinavir ’96: NVP, IDV, RIT ’92 AIDS ’96 HIV leading cause viral load of death approved adults 25-44 yrs old AIDS Deaths Red down Ribbon 40% due Tony to Awards HAART 19901 1994 1995 ‘96 My Pt was diagnosed HIV+ AN AIDS TIMELINE: THE 3rd Decade … GEORGE W. BUSH BARACK H. OBAMA 2001-2008 2009 - 2016 ’00 ’01 ’03 ‘04 ’05 ‘06 Darunavir ’07 ’08 Trizivir Tenofo Fuzeon Truvada Tipranavir Maraviroc Etravirine -Atripla vir Raltegravir Lopinavir ’00 13th Int’l AIDS : Conf in PEPFAR 25 30 Durban SA $15B/5 yrs years years 2000 AN AIDS TIMELINE: THE 4th Decade … DONALD J. -
Long-Acting Subcutaneous Lenacapavir Dosed Every 6 Months
Long-acting Subcutaneous Lenacapavir Dosed Every 6 Months as part of a Combination Regimen in Treatment-Naïve People with HIV: Interim 16-week Results of a Randomized, Open-label, Phase 2 Induction-Maintenance Study (CALIBRATE) Samir K. Gupta,1 Mezgebe Berhe,2 Gordon Crofoot,3 James Sims,4 Paul Benson,5 Moti Ramgopal,6 William E. Sanchez,7 Peter Ruane,8 Cheryl McDonald,9 Anita Scribner,10 Hui Wang,11 Laurie VanderVeen,11 Hadas Dvory-Sobol,11 Robert H. Hyland,11 Martin S. Rhee,11 Jared M. Baeten,11 Diana M. Brainard,11 Ellen Koenig12 1Indiana University School of Medicine, Indianapolis, USA; 2North Texas Infectious Diseases Consultants, Dallas, USA; 3The Crofoot Research Center, Inc., Houston, USA; 4St. Hope Foundation, Bellaire, USA; 5Be Well Medical Center, Berkley, USA; 6Midway Specialty Care Center, Fort Pierce, USA; 7Floridian Clinical Research, Hialeah, USA; 8Ruane Clinical Research Group, Los Angeles, USA; 9Texas Centers for Infectious Disease Associates, Fort Worth, USA; 10Diagnostic Clinic of Longview Center for Clinical Research, Longview, USA; 11Gilead Sciences Inc., Foster City, USA; 12Instituto Dominicano de Estudios Virológicos, Santo Domingo, Dominican Republic Disclosures SKG receives unrestricted research grant support from the NIH, Indiana University School of Medicine, and GSK/ViiV and receives advisory board fees from Gilead Sciences, Inc., and GSK/ViiV. 2 Acknowledgments We extend our thanks to: The study participants and their families Participating study investigators and staff: Dominican Republic: E Koenig United States: P Benson; DS Berger; M Berhe; C Brinson; P Cook; DR Coulston; GE Crofoot; FA Cruickshank; D Cunningham; E DeJesus; C Dietz; V Drelichman; E Gardner; A Gaur; D Goldstein; SK Gupta; D Hagins; R Hengel; T Hodge; C-B Hsiao; A Khalsa; CA Kinder; P Kumar; C McDonald; A Mills; JO Morales-Ramirez; C Newman; G Oguchi; O Osiyemi; MN Ramgopal; PJ Ruane; W Sanchez; JL Santana-Bagur; L Santiago; A Scribner; J Sims; GI Sinclair; JL Stephens; M Wohlfeiler; AK Wurapa This study was funded by Gilead Sciences, Inc. -
The CCR5-Delta32 Variant Might Explain Part of the Association Between COVID-19 and the Chemokine-Receptor Gene Cluster
medRxiv preprint doi: https://doi.org/10.1101/2020.11.02.20224659; this version posted November 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. The CCR5-delta32 variant might explain part of the association between COVID-19 and the chemokine-receptor gene cluster 1,8,12* 1,8* 2,8,9,10,11 Juan Gómez, Elías Cuesta-Llavona, Guillermo M. Albaiceta, Marta 3 4,8,9,12 2,8,10,11 García-Clemente, Carlos López-Larrea, Laura Amado-Rodríguez, Inés 8,10 3 3 1,8 1,8 López-Alonso, Tamara Hermida, Ana I. EnrÍquez, Helena Gil , Belén Alonso, 1,8 1 1,8,9,12 Sara Iglesias, Beatriz Suarez-Alvarez,4,8,12 Victoria Alvarez, Eliecer Coto *These authors contributed equally to this work. 1 Genética Molecular, Hospital Universitario Central Asturias, Oviedo, Spain. 2 Unidad de Cuidados Intensivos Cardiológicos, Hospital Universitario Central Asturias, Oviedo, Spain. 3 Neumología, Hospital Universitario Central Asturias, Oviedo, Spain. 4 Inmunología, Hospital Universitario Central Asturias, Oviedo, Spain. 5 Urgencias, Hospital Universitario Central Asturias, Oviedo, Spain. 8 Instituto de Investigación Sanitaria del Principado deAsturias, ISPA, Oviedo, Spain. 9 Universidad de Oviedo, Oviedo, Spain. 10 CIBER-Enfermedades Respiratorias. Instituto de Salud Carlos III. Madrid, Spain. 11 Instituto Universitario de Oncología del Principado de Asturias. Oviedo, Spain. 12 Red de Investigación Renal (REDINREN), Madrid, Spain. Correspondenceto: Dr.EliecerCoto Hospital Univ. Central Asturias 33011 – Oviedo – Spain Tel. 34.985.10.55.00 Email: [email protected] 1 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. -
TROGARZO (Ibalizumab-Uiyk) RATIONALE for INCLUSION IN
TROGARZO (ibalizumab-uiyk) RATIONALE FOR INCLUSION IN PA PROGRAM Background Trogarzo (ibalizumab-uiyk) is a recombinant humanized monoclonal antibody that blocks HIV-1 from infecting CD4+ T-cells. This medication blocks the HIV-1 virus from entering the host cell by interfering with post-attachment steps required for the entry of HIV-1 virus that occurs via cell fusion. The binding specificity of ibalizumab-uiyk to domain 2 of CD4 allows ibalizumab-uiyk to block viral entry into host cells without causing immunosuppression (1). Regulatory Status FDA approved indication: Trogarzo, a CD4-directed post-attachment HIV-1 inhibitor, in combination with other antiretroviral(s), is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen (1). Immune reconstitution inflammatory syndrome has been reported in one patient treated with Trogarzo in combination with other antiretrovirals. During the initial phase of combination antiretroviral therapies, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections, which may necessitate further evaluation and treatment(1). Phenotypic and genotypic test results revealed no evidence of cross-resistance between ibalizumab-uiyk and any of the approved classes of anti-retroviral drugs (CCR5 co-receptor antagonists, gp41 fusion inhibitors, integrase strand transfer inhibitors [INSTIs], non-nucleos(t)ide reverse transcriptase inhibitors [NNRTIs], nucleos(t)ide reverse transcriptase inhibitors [NRTIs], or protease inhibitors [PIs]). Ibalizumab-uiyk is active against HIV-1 resistant to all approved antiretroviral agents and exhibits antiretroviral activity against R5-tropic, X4-tropic, and dual-tropic HIV-1 (1). -
What's New in Hiv? Highlights & New Data on Hiv Treatment a Presentation for Healthtrust Members June 18, 2021
WHAT'S NEW IN HIV? HIGHLIGHTS & NEW DATA ON HIV TREATMENT A PRESENTATION FOR HEALTHTRUST MEMBERS JUNE 18, 2021 SHIVANI PATEL, PHARMD PGY-1 PHARMACY RESIDENT ROBERT WOOD JOHNSON UNIVERSITY HOSPITAL NAVANEETH NARAYANAN, PHARMD, MPH, BCIDP CLINICAL ASSOCIATE PROFESSOR RUTGERS UNIVERSITY ERNEST MARIO SCHOOL OF PHARMACY CONFLICT OF INTEREST DISCLOSURE There are no relevant financial interest to disclose for myself or my spouse/partner within the last 12 months. The preceptor has a financial interest/arrangement, affiliation or relationship with Astellas and Merck that could be perceived as a real or apparent conflict of interest in the context of the subject of this activity. Note: This program may contain the mention of suppliers, brand products, services, or drugs presented in a case study or comparative format using evidence-based research. Such examples are intended for educational and informational purposes only and should not be perceived as an endorsement of any particular supplier, brand, product, service or drug. 1 2 3 LEARNING Identify new antiretroviral Describe a two-drug regimen Outline key counseling points agents and their role in the for treatment-naïve to a patient receiving new OBJECTIVES management of HIV/AIDS individuals and factors to antiretroviral agents related consider when selecting an to drug administration, initial regimen for an potential side effects, and individual. drug-drug interactions DRUG NAME ABBREVIATIONS Abbreviation Full Name Abbreviation Full Name Abbreviation Full Name 3TC Lamivudine DTG Dolutegravir -
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 -
Evaluating the Pressor Effects of Drugs & Ambulatory Blood
Characterizing FDA’s Approach to Benefit-Risk Assessment throughout the Medical Product Life Cycle Tommy Douglas Conference Center • Silver Spring, MD May 16th, 2019 9:00 am – 4:55 pm Contents 2 Welcome & Overview Dr. Mark McClellan, MD, PhD, Director, Duke-Margolis Center for Health Policy 9:00 am – 9:05 am Electronic Comments Federal eRulemaking Portal Docket ID: FDA-2019-N-1468 Due June 17, 2019 11:59 PM ET www.regulations.gov/docket?D=FDA-2019-N-1468 Opening Remarks Theresa Mullin, PhD, Associate Director for Strategic Initiatives Center for Drug Evaluation and Research (CDER) 9:05 am – 9:15 am Applying Framework for Benefit-Risk Assessment Throughout the Human Drug Life Cycle Opening Remarks Theresa Mullin, PhD Associate Director Strategic Initiatives FDA Center for Drug Evaluation and Research May 16, 2019 Context • FDA qualitative structured B-R framework – primarily discussed in context of premarket assessment • PDUFA VI (FDARA 2017) enhancing benefit-risk assessment in regulatory decision-making • FDA will further the agency’s implementation of structured benefit-risk assessment, including the incorporation of the patient’s voice in drug development and decision- making, in the human drug review program • FY 2019 --FDA will convene a meeting, conducted through a qualified third party, to gather industry, patient, researcher, and other stakeholder input on key topics. • Including applying the benefit-risk framework throughout the human drug lifecycle, including best approaches to communicating FDA’s benefit-risk assessment • FY -
Guidelines for the Use of Antiretroviral Agents in Adults and Adolescent Living With
Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Developed by the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents – A Working Group of the Office of AIDS Research Advisory Council (OARAC) How to Cite the Adult and Adolescent Guidelines: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. Available at https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/ AdultandAdolescentGL.pdf. Accessed [insert date] [insert page number, table number, etc. if applicable] It is emphasized that concepts relevant to HIV management evolve rapidly. The Panel has a mechanism to update recommendations on a regular basis, and the most recent information is available on the HIVinfo Web site (http://hivinfo.nih.gov). What’s New in the Guidelines? August 16, 2021 Hepatitis C Virus/HIV Coinfection • Table 18 of this section has been updated to include recommendations regarding concomitant use of fostemsavir or long acting cabotegravir plus rilpivirine with different hepatitis C treatment regimens. June 3, 2021 What to Start • Since the release of the last guidelines, updated data from the Botswana Tsepamo study have shown that the prevalence of neural tube defects (NTD) associated with dolutegravir (DTG) use during conception is much lower than previously reported. Based on these new data, the Panel now recommends that a DTG-based regimen can be prescribed for most people with HIV who are of childbearing potential. Before initiating a DTG-based regimen, clinicians should discuss the risks and benefits of using DTG with persons of childbearing potential, to allow them to make an informed decision.