With latest 18-month data cut, Takeda pushes toward 2021 launch of dengue vaccine — can they sidestep Sanofi's disaster?
Takeda’s dengue vaccine has passed the second of a three-part late-stage test, the company says, buffing up a data package that they expect to take to regulators late next year — but raising concerns around a particular subgroup and falling efficacy rates.
At 18 months after the second dose, investigators are tracking an overall efficacy rate of 73% — down from the 80.2% reported at the 12-month time point. But equally significant are the secondary endpoints measuring clinical implications, said Derek Wallace, the global dengue lead.
“The key one is hospitalization and we saw a reduction of 90% in dengue required hospitalization,” he said. “We met in fact all of our secondary efficacy endpoints for which we have enough cases.”
In all, Takeda plans to follow these 19,000 plus patients for three more years, compiling more safety data for review on an annual basis.
On top of the 90.4% efficacy against hospitalized dengue (p<0.001), the vaccine — TAK-003 — also conferred statistically significant effects on dengue hemorrhagic fever (85.9%). There weren’t sufficient number of severe virologically-confirmed dengue (VCD) to determine whether that measure had been met.
At the American Society of Tropical Medicine and Hygiene conference, where Takeda is presenting the data, researchers will also break down the numbers by subgroups. One of them is particularly important for Rajeev Venkayya, president of the vaccine business unit: the baseline seronegative population, or children who had not had a previous dengue infection before getting vaccinated. Overall efficacy in that group was 66.2% versus 76.1% among the seropositive.
Longtime observers of the field remember the crisis Sanofi faced around Dengvaxia, the first-ever dengue vaccine, after a mass vaccination scheme in the Philippines confirmed experts’ warnings that it could increase the risk of severe dengue infection in those who have never been exposed to the virus. This is because their bodies would likely treat the first real dengue infection as their second, which tends to trigger more fierce reactions, thanks to the vaccine.
Without specifically naming Sanofi, Venkayya alluded to that episode, emphasizing that their vaccine is emerging “as a potentially very, very important tool to control dengue.”
“You can ascertain whether they’re been exposed to dengue in the past or not, but we find that in both the seropositive and the seronegative populations, the performance is very strong,” he said.
Despite the overall numbers, though, Takeda didn’t quite manage a clean slate on the seronegative side. Specifically, the efficacy against dengue serotype 3 in kids who have never been infected before was “statistically inconclusive but suggests a lack of efficacy,” the company wrote in its release.
The efficacy for dengue 3 registered at 48.9%, compared to 69.8% for dengue 1 and 95.1% for dengue 2. In the 12-month analysis, the numbers for serotypes 1, 2 and 3 were 73.7%, 97.7% and 62.6% respectively. There still weren’t enough dengue 4 cases to draw conclusions.
Here’s the breakdown of the cases recorded in the study, where patients were randomized 2:1 to receive the vaccine or placebo, per Takeda:
For dengue serotype 1, there were 38 cases of VCD in the vaccine group (21 seropositive, 17 seronegative) and 62 cases in the placebo group (37 seropositive, 25 seronegative). For dengue serotype 2, there were 8 cases in the vaccine group (7 seropositive, 1 seronegative) and 80 cases in the placebo group (54 seropositive, 26 seronegative). For dengue serotype 3, there were 63 cases in the vaccine group (43 seropositive, 20 seronegative) and 60 in the placebo group (54 seropositive, 6 seronegative). Finally, for dengue serotype 4, there were 5 cases each in the vaccine (4 seropositive, 1 seronegative) and placebo groups (all seropositive).
Anna Durbin, a professor at the Johns Hopkins Bloomberg School of Public Health, called that lack of efficacy in dengue 3 seronegatives “worrisome” but told the Wall Street Journal that “Overall, the efficacy is very good and higher than that seen with (Sanofi’s) Dengvaxia, which is encouraging.”
It makes sense for the serotype 2 cohort to stand out, Wallace explained, as the vaccine is based on an attenuated dengue 2 virus. Given heightened sensitivities, the “extra cases of fever” among seronegative individuals later hit with dengue 3 is something that Wallace plans to work through with the scientific community and regulators in both dengue endemic countries and the EMA, where they plan to seek a review under Article 58, a pathway designed to lend the European agency’s scientific authority to medicines used outside the EU.
“I think it’s important to consider the disease that we’re going to fight with the vaccine,” he said, as the mosquito-born ailment affects an estimated 40% of the world’s population, has been named by the WHO as one of the top 10 threats to global health and is still rapidly expanding despite efforts to contain it.
While the team preps their dossier, Takeda has already enlisted a contract manufacturer to produce the first batch of commercial vaccines for a planned 2021 launch. It has also opened a bespoke €130 million plant in Germany, Venkayya added.