The US Food and Drug Administration (FDA) dealt Sanofi’s dengue fever vaccine a serious blow when an advisory committee failed to fully endorse the vaccine’s efficacy and safety as part of a licence approval process.

On 7 March, the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) issued a split decision on Dengvaxia (dengue tetravalent vaccine [live, attenuated]), regarding a Biologics License Application’s (BLA’s) for its proposed patient population of individuals 9-45 years of age who have previously been exposed to dengue virus (DENV) serotypes 1–4 and live in endemic areas.

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Sanofi’s dengue vaccine setback

With an FDA decision on Sanofi’s BLA for Dengvaxia expected by 1 May, the VRBPAC’s opinion all but guarantees a narrow label for Dengvaxia in the US – a further setback for the once-promising, first-in-class franchise.

On the question of Dengvaxia’s efficacy and safety in DENV-experienced individuals 9-45 years of age, VRBPAC voters were split, instead of viewing its performance in DENV-experienced individuals 9-17 years of age – a much narrower indication than that proposed by Sanofi in the BLA – more favourably.

The table below summarises the VRBPAC’s voting on Dengvaxia by affected age group.

Dengvaxia VRBPAC voting result

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Source: GlobalData.  Note: FDA’s VRBPAC meeting was held on 7 March 2019. 

The VRBPAC’s reluctance to endorse the BLA’s proposed target population of 9-45 years of age contradicts a recent decision from the European Commission from December 2018 which granted the broader market authorisation to Dengvaxia for the prevention of dengue infection in DENV-experienced individuals 9-45 years of age who are living in endemic areas.

While it is not uncommon for US and EU regulators to issue conflicting recommendations on proposed indications and/or approved drug labels – especially when there are notable differences in disease epidemiology – in this case, they speak to the dearth of strong clinical evidence supporting Dengvaxia’s use in these populations.

Sanofi’s dengue vaccine US-EU consensus

Another more daunting hurdle for Sanofi to overcome is the fact that consensus between the FDA and European Medicines Agency does exist regarding the ineffectiveness of Dengvaxia in DENV-naïve patients, a characteristic that severely hampers its usefulness outside of dengue-endemic areas.

From a commercial standpoint, this not only precludes Dengvaxia from being used as a routine shot for children under 9 years of age in endemic areas, but also prohibits its use as a travelers’ vaccine in North America and Europe, which represents a lucrative long-term segment of the dengue vaccine market given the disease’s current epidemiology.

In addition to hindering its own commercial potential, Dengvaxia’s clinical shortcomings have virtually erased its first-to-market advantage, opening it up to competition from later entrants.

Of the vaccines in late-stage clinical development, GlobalData believes that Takeda’s TAK-003 and the National Institutes of Health (NIH)/Instituto Butantan’s TV-003 are the most promising.

In addition to boasting solid clinical data to date, both TAK-003 and TV-003 feature alternative vaccine design strategies – a DENV-DENV chimera and targeted mutagenesis, respectively – that theoretically should allow them to circumvent Dengvaxia’s efficacy and safety issues, according to key opinion leaders interviewed by GlobalData.

With inherent efficacy issues in key patient populations limiting its usefulness and negating its first-to-market advantage, Dengvaxia’s position was arguably untenable before the VRBPAC’s narrower-than-expected indication recommendations.

Sanofi’s dengue vaccine impact

Even if Sanofi receives FDA approval for Dengvaxia, the impact of this licensure will be minimal given the relatively small US population segments that this restricted label encompass.

GlobalData believes that in order to rescue Dengvaxia from this downward spiral, Sanofi must review all available clinical data and consider additional clinical trials to highlight any bright spots in its clinical profile. Otherwise, it may be time for the vaccine giant to cut its losses and jettison Dengvaxia for good.

Related reports: 
GlobalData (2019). Takeda’s TAK-003 Achieves Phase III Primary Endpoint, Putting Dengvaxia on Even Thinner Ice, January 2019, GDHC2233EI

GlobalData (2018). EMA Approval of Dengvaxia, Though Positive, Will Not Reverse Its Dwindling Commercial Prospects, December 2018, GDHC2187EI