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Collated by Gary G. Kohls, MD for Research Purposes – February 17, 2021 (1917 words)

1.  Safety and Efficacy of the BNY162b2 Covid-19 Vaccine (hizer-BioNTech's mRNA vaccine)

N Engl J MedDecember 20, 2020; 383:2603-2615

By Fernando P. Polack, M.D., Stephen J. Thomas, M.D., Nicholas Kitchin, M.D., Judith Absalon, M.D., Alejandra Gurtman, M.D., Stephen Lockhart, D.M., John L. Perez, M.D., 

Gonzalo Pérez Marc, M.D., Edson D. Moreira, M.D., Cristiano Zerbini, M.D., Ruth Bailey, B.Sc., Kena A. Swanson, Ph.D., et al., for the C4591001 Clinical Trial Group*

https://www.nejm.org/doi/full/10.1056/NEJMoa2034577?query=recirc_mostViewed_railB_article

Abstract

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently.

Methods

In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety.

Results

A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups.

Conclusions

A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728. opens in new tab.)

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Supported by BioNTech and Pfizer.

Conflict of InterestDisclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Polack and Thomas contributed equally to this article.

This article was published on December 10, 2020, and updated on December 16, 2020, at NEJM.org.

data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank all the participants who volunteered for this study; and the members of the C4591001 data and safety monitoring board for their dedication and their diligent review of the data.

We also acknowledge the contributions of the C4591001 Clinical Trial Group (see the Supplementary Appendix); Tricia Newell and Emily Stackpole (ICON, North Wales, PA) for editorial support funded by Pfizer; and the following Pfizer staff: Greg Adams, Negar Aliabadi, Mohanish Anand, Fred Angulo, Ayman Ayoub, Melissa Bishop-Murphy, Mark Boaz, Christopher Bowen, Salim Bouguermouh, Donna Boyce, Sarah Burden, Andrea Cawein, Patrick Caubel, Darren Cowen, Kimberly Ann Cristall, Michael Cruz, Daniel Curcio, Gabriela Dávila, Carmel Devlin, Gokhan Duman, Niesha Foster, Maja Gacic, Luis Jodar, Stephen Kay, William Lam, Esther Ladipo, Joaquina Maria Lazaro, Marie-Pierre Hellio Le Graverand-Gastineau, Jacqueline Lowenberg, Rod MacKenzie, Robert Maroko, Jason McKinley, Tracey Mellelieu, Farheen Muzaffar, Brendan O’Neill, Jason Painter, Elizabeth Paulukonis, Allison Pfeffer, Katie Puig, Kimberly Rarrick, Balaji Prabu Raja, Christine Rainey, Kellie Lynn Richardson, Elizabeth Rogers, Melinda Rottas, Charulata Sabharwal, Vilas Satishchandran, Harpreet Seehra, Judy Sewards, Helen Smith, David Swerdlow, Elisa Harkins Tull, Sarah Tweedy, Erica Weaver, John Wegner, Jenah West, Christopher Webber, David C. Whritenour, Fae Wooding, Emily Worobetz, Xia Xu, Nita Zalavadia, Liping Zhang, the Vaccines Clinical Assay Team, the Vaccines Assay Development Team, and all the Pfizer colleagues not named here who contributed to the success of this trial. We also acknowledge the contributions of the following staff at BioNTech: Corinna Rosenbaum, Christian Miculka, Andreas Kuhn, Ferdia Bates, Paul Strecker, Ruben Rizzi, Martin Bexon, Eleni Lagkadinou, and Alexandra Kemmer-Brück; and the following staff at Polymun: Dietmar Katinger and Andreas Wagner.

 

Author Affiliations

From Fundacion INFANT (F.P.P.) and iTrials-Hospital Militar Central (G.P.M.), Buenos Aires; State University of New York, Upstate Medical University, Syracuse (S.J.T.), and Vaccine Research and Development, Pfizer, Pearl River (J.A., A.G., K.A.S., K.K., W.V.K., D.C., P.R.D., K.U.J., W.C.G.) — both in New York; Vaccine Research and Development, Pfizer, Hurley, United Kingdom (N.K., S.L., R.B.); Vaccine Research and Development (J.L.P., P.L.) and Worldwide Safety, Safety Surveillance and Risk Management (S.M.), Pfizer, Collegeville, PA; Associação Obras Sociais Irmã Dulce and Oswaldo Cruz Foundation, Bahia (E.D.M.), and Centro Paulista de Investigação Clinica, São Paulo (C.Z.) — both in Brazil; Global Product Development, Pfizer, Peapack, NJ (S.R.); Cincinnati Children’s Hospital, Cincinnati (R.W.F.); Johns Hopkins Bloomberg School of Public Health, Baltimore (L.L.H.); BioNTech, Mainz (ÖT., U.Ş.), and Medizentrum Essen Borbeck, Essen (A.S.) — both in Germany; Tiervlei Trial Centre, Karl Bremer Hospital, Cape Town, South Africa (H.N.); Hacettepe University, Ankara, Turkey (S.Ü.); and Worldwide Safety, Safety Surveillance and Risk Management, Pfizer, Groton, CT (D.B.T.).

Address reprint requests to Dr. Absalon at Pfizer, 401 N. Middletown Rd., Pearl River, NY 10965, or at judith.absalon@pfizer.com.

The raw research data for the Pfizer-BioNTech mRNA vaccine is available at: https://www.nejm.org/doi/suppl/10.1056/NEJMoa2034577/suppl_file/nejmoa2034577_appendix.pdf

The raw research data for the Moderna mRNA vaccine is available at: https://www.nejm.org/doi/suppl/10.1056/NEJMoa2035389/suppl_file/nejmoa2035389_appendix.pdf

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2} “Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents” (Genentech/Roche’s Xofluza)

 


N Engl J MedSeptember 6, 2018; 379:913-923

 

By Frederick G. Hayden, M.D., Norio Sugaya, M.D., Nobuo Hirotsu, M.D., Ph.D., Nelson Lee, M.D., Menno D. de Jong, M.D., Ph.D., Aeron C. Hurt, Ph.D., Tadashi Ishida, M.D., Ph.D., Hisakuni Sekino, M.D., Ph.D., Kota Yamada, M.D., Simon Portsmouth, M.D., Keiko Kawaguchi, M.Sc., Takao Shishido, Ph.D., et al., for the Baloxavir Marboxil Investigators Group*

 

https://www.nejm.org/doi/full/10.1056/NEJMoa1716197

 

Abstract

Background

Baloxavir marboxil (Xofluza)is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents.

Methods

We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016–2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population.

Results

In the phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P<0.05). In the phase 3 trial, the intention-to-treat infected population included 1064 patients; 84.8 to 88.1% of patients in each group had influenza A(H3N2) infection. The median time to alleviation of symptoms was 53.7 hours (95% confidence interval [CI], 49.5 to 58.5) with baloxavir, as compared with 80.2 hours (95% CI, 72.6 to 87.1) with placebo (P<0.001). The time to alleviation of symptoms was similar with baloxavir and oseltamivir. Baloxavir was associated with greater reductions in viral load 1 day after initiation of the regimen than placebo or oseltamivir. Adverse events were reported in 20.7% of baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir recipients. The emergence of polymerase acidic protein variants with I38T/M/F substitutions conferring reduced susceptibility to baloxavir occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 trial and phase 3 trial, respectively.

Conclusions

Single-dose baloxavir was without evident safety concerns, was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing the viral load 1 day after initiation of the trial regimen in patients with uncomplicated influenza. Evidence for the development of decreased susceptibility to baloxavir after treatment was also observed. (Funded by Shionogi; JapicCTI number, 153090, and CAPSTONE-1 ClinicalTrials.gov number, NCT02954354. opens in new tab.)

 

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Supported by Shionogi.

Conflict of Interest Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Dr. Hayden reports receiving consulting fees, paid to the Robert Ford Haitian Orphanage and School Foundation, from Shionogi, Seqirus, and PrEP Biopharm, receiving fees for serving on a data and safety monitoring board, paid to the University of Virginia, from GlaxoSmithKline, receiving fees for serving as chair of a data and safety monitoring board, paid to the University of Virginia, from Celltrion and Vaccitech, receiving travel support from Shionogi, and serving as an unpaid consultant to Cocrystal Pharma, Farmak, Fujifilm/Toyama Chemical/MediVector, GlaxoSmithKline, Janssen, MedImmune, Regeneron, resTORbio, Roche/Genentech, Vir Biotechnology, and Visterra;

Dr. Sugaya, receiving lecture fees from Chugai Pharmaceutical, Daiichi Sankyo, Merck Sharp & Dohme, Astellas Pharma, and Denka Seiken and consulting fees and lecture fees from Shionogi;

Dr. Hirotsu, receiving consulting fees and lecture fees from Shionogi;

Dr. Lee, receiving consulting fees, lecture fees, and travel support from Seqirus and Janssen Pharmaceuticals;

Dr. de Jong, serving on an advisory board and receiving travel support and fees for serving on an independent data and safety monitoring board, paid to his institution (University of Amsterdam), from Janssen, serving on an advisory board and receiving travel support, paid to the University of Amsterdam, fromMedImmune, serving on an advisory board and receiving travel support from Shionogi, and serving on an independent data and safety monitoring board and receiving travel support, paid the University of Amsterdam, from GlaxoSmithKline and Vertex Pharmaceuticals;

Dr. Sekino, receiving grant support from Daiichi Sankyo;

Dr. Portsmouth, Ms. Kawaguchi, Dr. Shishido, Mr. Arai, and Dr. Uehara, being employed by Shionogi;

Mr. Tsuchiya, being employed by and holding stock in Shionogi; and

Dr. Watanabe, receiving consulting fees and lecture fees from Chugai Pharmaceutical, GlaxoSmithKline, Mitsubishi Tanabe Pharma, Janssen Pharmaceuticals, and Sumitomo Dainippon Pharma, grant support, consulting fees, and lecture fees from Daiichi Sankyo, grant support and lecture fees from Shionogi, grant support and consulting fees from Toyama Chemical, and grant support from Fujifilm Pharmaceuticals, Meiji Seika Pharma, and Kyorin Pharmaceutical.

No other potential conflict of interest relevant to this article was reported.

We thank the patients and investigators who participated in the two trials, and Lisa Cook (University of Virginia), Toshinari Ochi (Shionogi), and Wei Jiang (Shionogi) for their assistance in the preparation of an earlier version of the manuscript.

 

Author Affiliations

From the Department of Medicine,University of Virginia School of Medicine, Charlottesville, VA(F.G.H.); the Department of Pediatrics, Keiyu Hospital,Yokohama(N.S.), Hirotsu Clinic,Kawasaki(N.H.), the Department of Respiratory Medicine,Kurashiki Central Hospital, Kurashiki(T.I.), Sekino Hospital,Tokyo(H.S.), Tsuchiura Beryl Clinic, Tsuchiura(K.Y.), Shionogi,Osaka(K.K., T.S., M.A., K.T., T.U.), and the Research Division for Development of Anti-Infective Agents, Institute of Development, Aging, and Cancer, Tohoku University, Sendai (A.W.) — all inJapan; the Division of Infectious Diseases, Department of Medicine,University of Alberta, Edmonton, Canada(N.L.); the Department of Medical Microbiology, Academic Medical Center,University of Amsterdam, Amsterdam(M.D.J.); the Department of Microbiology and Immunology,University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC,Australia(A.C.H.); and Shionogi, Florham Park, New Jersey(S.P.).

Address reprint requests to Dr. Hayden at the Division of Infectious Diseases and International Health, University of Virginia Health System, P.O. Box 801342, Charlottesville, VA 22908, or at fgh@virginia.edu.

A complete list of the members of the Baloxavir Marboxil Investigators Group is provided in the Supplementary Appendix, available at NEJM.org.

Note: (A single dose of Genentech’s Xofluza costs $190 retail)