Twenty-six years after it began development, Sanofi’s dengue prevention vaccine Dengvaxia® (Dengue Tetravalent Vaccine, Live) has won FDA approval—albeit in a narrower patient population than what the pharma giant originally envisioned.

Dengvaxia won FDA authorization as the first vaccine approved for the prevention of dengue disease caused by all dengue virus serotypes (1, 2, 3, and 4) in people ages 9 through 16 who have laboratory-confirmed previous dengue infection and who live in endemic areas of the United States.

According to the FDA, dengue is endemic in the U.S. territories of American Samoa, Guam, Puerto Rico, and the U.S. Virgin Islands. Sanofi has cautioned that it is unknown whether Dengvaxia is safe or protective for people living in areas where dengue is not endemic who travel to dengue-endemic areas.

“Despite this public health threat, there is no treatment and there has been no previously approved vaccine available in these areas,” David Greenberg, MD, regional medical head North America, Sanofi Pasteur, said in a statement. “Today’s FDA approval of Dengvaxia allows us to bring a critical medical prevention tool to at-risk populations, helping combat and prevent dengue among children living in U.S. dengue-endemic areas.”

Sanofi began efforts to develop a dengue vaccine in 1993, and launched its clinical development of Dengvaxia in 2004—two years after the World Health Organization published guidelines for the clinical evaluation of dengue vaccines in endemic areas.

The U.S. approval comes four months after the European Commission in December 2018 granted marketing authorization for Dengvaxia to prevent dengue in individuals ages 9–45 living in endemic areas with a documented prior infection. In addition to the European Union, Dengvaxia has been approved in 19 countries in Latin America and Asia.

Sanofi’s vaccine unit Sanofi Pasteur initially sought approval for Dengvaxia in patients between ages 9 to 45. But among the 16 trials from which the company submitted efficacy, immunogenicity, and safety data to the FDA, three trials established the strongest safety and efficacy data for Dengvaxia in patients ages 9–16, according to the FDA.

76% Effective

In those three studies, Dengvaxia was determined to be approximately 76% percent effective in preventing symptomatic, laboratory-confirmed dengue disease in individuals ages 9–16 who previously had laboratory-confirmed dengue disease. The randomized, placebo-controlled studies involved approximately 35,000 individuals in dengue-endemic areas, including Puerto Rico, Latin America, and the Asia Pacific region.

One of the three studies pinpointed the ages 9–16 patient population: the Phase III CYD15 trial met its primary efficacy endpoint by showing 60.8% vaccine efficacy against symptomatic virologically-confirmed dengue (VCD) starting at >28 days after receipt of the final month-12 vaccination until month 25, Sanofi told the FDA, according to the FDA Briefing Document submitted for the March 7 meeting of the Vaccines and Related Biological Products Advisory Committee.

The Committee recommended against Sanofi’s vaccine in patients ages 9–16 by a 6 to 7 vote with one abstention, and deadlocked 7 to 7 on the safety of the vaccine in that original patient population. However, in the 9-to-16-year-old population, the Committee voted to recommend approval 13-1 based on the vaccine’s effectiveness, and 10-4 based on its safety. The FDA usually follows the recommendations of its advisory panels in deciding on new medicines and new indications for already-approved drugs.

The narrower patient population is likely to further lower Dengvaxia sales from initial estimates of a potential blockbuster. Dengvaxia racked up €3 million (approximately $3.4 million) in 2017 net sales, and Sanofi had not disclosed a 2018 figure in its announcement of fourth-quarter and full-year results.

Even worse for the company, in 2017 Sanofi took an €87 million ($97.3 million) “impairment of tangible assets” charge related to Dengvaxia, after long-term clinical trial data showed the vaccine could increase the severity of the disease in people who were not previously infected.

Indictment After 10 Deaths

The Philippines has permanently stopped Sanofi from selling, distributing, and marketing Dengvaxia, following 10 deaths that authorities said were connected to use of the dengue prevention vaccine.

Late last month, the country’s Department of Justice indicted Rose Capeding, 63, former head of the dengue department of the Research Institute for Tropical Medicine (RITM), who faces up to 48 years in prison. She was one of 20 people for whom the Philippines justice department had found probable cause for indictment for “reckless imprudence resulting [in] homicide” in February, accusing them of having “facilitated, with undue haste,” Dengvaxia’s approval and distribution to Philippine schoolchildren.

The 20 also included officials from Sanofi, as well as current and former Philippine health officials. Sanofi has objected to the justice department actions, and has promised to vigorously defend itself against charges.

While the first infection with dengue virus typically results in either no symptoms or a mild illness that can be mistaken for the flu or another viral infection, a subsequent infection can lead to severe dengue, including dengue hemorrhagic fever (DHF), a more severe form of the disease that can be fatal. Approximately 95% of all severe/hospitalized cases of dengue are associated with second dengue virus infection.

Because there are no specific drugs approved for the treatment of dengue disease, care is limited to the management of symptoms.

The U.S. Centers for Disease Control and Prevention (CDC) estimates that each year, an estimated 400 million dengue virus infections occur globally. Of these, approximately 500,000 cases develop into DHF, which contributes to about 20,000 deaths, primarily among children.

Peter Marks, MD, director of the FDA’s Center for Biologics Evaluation and Research, noted in an agency statement that infection by one type of dengue virus usually provides immunity against that specific serotype, but a subsequent infection by any of the other three serotypes of the virus increases the risk of developing severe dengue disease, which may lead to hospitalization or even death.

“As the second infection with dengue is often much more severe than the first, the FDA’s approval of this vaccine will help protect people previously infected with dengue virus from subsequent development of dengue disease,” Marks stated.

Said Anna Abram, FDA deputy commissioner for policy, legislation, and international affairs: “The FDA is committed to working proactively with our partners at the U.S. Centers for Disease Control and Prevention, as well as international partners, including the World Health Organization, to combat public health threats, including through facilitating the development and availability of medical products to address emerging infectious diseases.

“While there is no cure for dengue disease, today’s approval is an important step toward helping to reduce the impact of this virus in endemic regions of the United States,” Abram added.

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