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.

Derek Wal­lace

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.

Ra­jeev Venkayya

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.

Adap­tive De­sign Meth­ods Of­fer Rapid, Seam­less Tran­si­tion Be­tween Study Phas­es in Rare Can­cer Tri­als

Rare cancers account for 22 percent of cancer diagnoses worldwide, yet there is no universally accepted definition for a “rare” cancer. Moreover, with the evolution of genomics and associated changes in categorizing tumors, some common cancers are now characterized into groups of rare cancers, each with a unique implication for patient management and therapy.

Adaptive designs, which allow for prospectively planned modifications to study design based on accumulating data from subjects in the trial, can be used to optimize rare oncology trials (see Figure 1). Adaptive design studies may include multiple cohorts and multiple tumor types. In addition, numerous adaptation methods may be used in a single trial and may facilitate a more rapid, seamless transition between study phases.

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