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Background Analysis: US FDA Advisory Committee to Recommend Strains for the Next Influenza Virus Vaccine; Hear Overviews of CBER Research; Discuss Dengue Vaccine – MAR 6-7, 2019 (VRBPAC)

Announcement

The US FDA has scheduled a Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting for Wednesday to Thursday, March 6-7, 2019.

On March 6, 2019, under Topic I, the committee will discuss and make recommendations on the selection of strains to be included in the influenza virus vaccines for the 2019 to 2020 influenza season in the Northern Hemisphere.

On March 6, 2019, under Topic II, the committee will hear an overview of the research programs in the Laboratory of Immunoregulation (LIR) and the Laboratory of Retroviruses (LR), Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research (CBER), FDA.

On March 7, 2019, under Topic III, the committee will make recommendations on the safety and effectiveness of Dengue Tetravalent Vaccine (Live, Attenuated) (DENGVAXIA) manufactured by Sanofi Pasteur (Sanofi).

Topic I: Influenza Virus Vaccine

Indication Background

Description of Indication

Influenza is a contagious respiratory illness caused by influenza viruses that infect the respiratory tract. It can cause mild to severe illness, and at times can lead to death. Seasonal influenza is characterized by a sudden onset of high fever, dry cough, headache, sore throat, muscle and joint pain, and severe malaise.

Most people recover within a week without requiring medical attention. However, some people, including older people, young children, and people with certain health conditions, such as chronic heart, lung, kidney, liver, blood or metabolic diseases or weakened immune systems, are at high risk for serious flu complications. Influenza virus infections can cause primary influenza viral pneumonia; exacerbate underlying medical conditions (e.g., pulmonary or cardiac disease); lead to secondary bacterial pneumonia, sinusitis, or otitis media; or contribute to co-infections with other viral or bacterial pathogens. In the United States, on average 5% to 20% of the population gets the flu, and more than 200,000 people are hospitalized from seasonal flu-related complications annually.

There are three types of influenza viruses: A, B and C. Type C infections cause a mild respiratory illness and are not thought to cause epidemics: Human influenza A and B viruses cause seasonal epidemics of disease.

In temperate climates, seasonal epidemics occur mainly during winter months. In the Northern Hemisphere, the flu season can begin as early as October and can last as late as April or May. In the temperate regions of the Southern Hemisphere, influenza activity typically occurs during April – September.

Influenza A viruses are divided into subtypes based on two proteins on the surface of the virus: the hemagglutinin (H) and the neuraminidase (N). There are 17 different hemagglutinin subtypes and 10 different neuraminidase subtypes. Influenza A viruses can be further broken down into different strains. Influenza B viruses are not divided into subtypes, but can be further broken down into different strains. Changes in influenza viruses occur in two ways: antigenic drift, small changes that happen continually over time; and antigenic shift, which is an occasional, abrupt, major change in influenza A viruses, resulting in new hemagglutinin and/or new hemagglutinin and neuraminidase proteins. Type A viruses undergo both kinds of changes; influenza type B viruses change only by the more gradual process of antigenic drift.

Product Background

Description of Product

The following injectable vaccines are FDA-approved:

    AFLURIA by Seqirus Pty. Ltd.

    Agriflu by Novartis Vaccines and Diagnostics, Inc.

    FluLaval by ID Biomedical Corporation of Quebec

    Fluarix by GlaxoSmithKline Biologicals

    FluBlok by Protein Sciences Corporation

    Flucelvax by Seqirus, Inc.

    Fluvirin by Seqirus Vaccines Limited

    Fluzone by Sanofi Pasteur, Inc., which also available for intradermal administration

    Fluad (adjuvanted) by Seqirus, Inc

An intranasal vaccine, called FluMist, by Medimmune, LLC, is also FDA-approved.

Regulatory Background

The viruses to be included in the vaccine can change each year, based on international surveillance and scientists’ estimations about which types and strains of viruses will circulate in a given year. Each year, the FDA's VRBPAC meets once to select the influenza viruses for the composition of the influenza vaccine for the next US influenza season and once to select the influenza virus strains for the next Southern Hemisphere vaccine. During thes meetings, the advisory committee reviews and evaluates the surveillance data related to epidemiology and antigenic characteristics of recent influenza isolates, serological responses to previous vaccines, and the availability of candidate strains and reagents. In the past, the committee made recommendations of two A strains, usually A/H1N1, A/H3N2, and one B strain, to be included in a trivalent vaccine. More recently, they have also voted on an additional B strain to be included in a quadrivalent vaccine.

Tarius expects that the FDA will review the recommendations of the World Health Organization (WHO) recommendations at the upcoming VRBPAC meeting.

Topic II: Overview of CBER Research

Under Topic II, the committee will hear an overview of the research programs in the Laboratory of Immunoregulation (LIR) and the Laboratory of Retroviruses (LR), Division of Viral Products, Office of Vaccines Research and Review, CBER, FDA.

Topic III: Overview of CBER Research

Under Topic III, the committee will make recommendations on the safety and effectiveness of Dengue Tetravalent Vaccine (Live, Attenuated) (DENGVAXIA) manufactured by Sanofi Pasteur.

Indication Background

Description of Indication

Dengue fever is a virus transmitted by the bite of infected Aedes aegypti mosquitoes. Symptoms include a high fever, headaches, joint and muscle pain, vomiting, and a rash. Occasionally, there is mild bleeding from the nose or gums or signs of bruising. Severe dengue may include much more severe bleeding from internal organs, failure of multiple internal organs such as the liver, even without bleeding, and shock, any of which may be life-threatening. There are four different serotypes of dengue virus (DENV1-4), and because a primary infection with any one serotype can eventually lead to severe disease after infection with a second serotype, all vaccines under development aim to protect against all four serotypes simultaneously.  For this reason, the study vaccine consists of a mixture of four dengue viruses, one for each serotype, and each virus has been attenuated (weakened). The intent of the vaccine is to cause an infection in the vaccinated person that results in protective immunity without causing signs of disease.

In the US, dengue is endemic in the territories of Puerto Rico and the US Virgin Islands.

Product Background

DENGVAXIA is a live recombinant tetravalent dengue vaccine developed by Sanofi. It is proposed to be dosed three times on a 0/6/12-month schedule. A biologics license application (BLA) for DENGVAXIA is currently under review at the FDA. It is approved elsewhere (see section, Regulatory Background).

DENGVAXIA has been evaluated in two Phase 3 clinical trials in more than 35,000 participants aged 2 to 16 years. In each of these trials, participants were randomized to vaccine and placebo in a 2:1 ratio. The study protocols included an active phase of follow-up for one year after the last dose of vaccine in the series (25 months from dose 1) and included a hospital-based follow-up period of four additional years, which is ongoing.

Within the randomized subset of participants for whom pre-vaccination blood samples were collected, pooled vaccine efficacy against virologically confirmed dengue (VCD) in those seropositive for a prior exposure to dengue virus was 78.2%, while in those seronegative at baseline it was 38.1% (not statistically significant).

On November 29, 2017, Sanofi announced the results of additional studies to better describe the benefit-risk in seronegative individuals. This was made possible through the use of a newly developed nonstructural protein 1-based (NS1-based) antibody assay applied to blood samples taken 13 months after vaccination to retrospectively infer dengue serostatus at time of first vaccination.

The new analyses from the long-term safety follow-up indicated that:

·      Overall population level benefit of vaccination remains favorable, but the vaccine performs differently in seropositive versus seronegative individuals.

·      Vaccine efficacy (VE) against virologically confirmed symptomatic dengue was high among inferred baseline seropositive participants ≥9 years of age: 76% (95%CI: 63.9, to 84.0), but much lower among baseline seronegative participants: 38.8% (95%CI: –0.9 to 62.9%) in the first 25 months after the first dose of vaccine.

·      There is an increased risk of hospitalization and severe dengue in seronegative individuals starting about 30 months after the first dose.

·      In areas of 70% dengue seroprevalence, over a 5-year follow-up, for every 4 severe cases prevented in seropositive individuals, there would be one excess severe case in seronegative individual per 1,000 vaccinees; for every 13 hospitalizations prevented in seropositive vaccinees, there would be 1 excess hospitalization in seronegative vaccinees per 1,000 vaccinees.

(SOURCE: World Health Organization website: Questions and Answers on Dengue Vaccines)

Regulatory Background

US Regulatory Background

May 1, 2019 – PDUFA date

October 30, 2018 – Sanofi announced the acceptance of the DENGVAXIA BLA.

Priority Review

Ex-US Regulatory Background

DENGVAXIA is the first dengue vaccine to be licensed. It was first licensed in Mexico in December 2015 for use in individuals 9-45 years of age living in endemic areas, and is now licensed in 20 countries. It was recently authorized by the European Medicines Agency (EMA) on December 18, 2018.

Approximately five additional dengue vaccine candidates are in clinical development, with two candidates (developed by the National Institutes of Health (NIH)/Butantan Institute and Takeda) now in Phase III trials.

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Sanofi Pasteur Drug Name: Dengue Tetravalent Vaccine (Live, Attenuated) none Drug Class: vaccine Indication: dengue, influenza


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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.