Sanofi’s be­lat­ed ad­mis­sion of a lethal Deng­vax­ia threat came long af­ter mul­ti­ple high-pro­file warn­ings

Philip­pine health of­fi­cials ad­min­is­ter­ing Deng­vax­ia ear­li­er this year Sipa, AP Im­ages


Late last week, the Philip­pine gov­ern­ment woke up to a pub­lic health cri­sis it had played a ma­jor role in cre­at­ing.

It be­gan on April 4 last year, when health of­fi­cials launched a dengue vac­ci­na­tion pro­gram that would ag­gres­sive­ly seek out more than 700,000 peo­ple — in­clud­ing tens of thou­sands of chil­dren 9 and up — for $70 mil­lion worth of Sanofi’s new­ly ap­proved Deng­vax­ia.

But last week, Sanofi — which her­ald­ed Phase III da­ta in 2015 that CEO Olivi­er Brandi­court de­clared was an “his­toric” achieve­ment for a like­ly block­buster prod­uct — said there was a prob­lem with its vac­cine. The phar­ma gi­ant an­nounced some­thing that had al­ready been clear­ly fore­told in two stud­ies by not­ed dengue ex­perts be­fore and right af­ter the Philip­pine De­part­ment of Health be­gan in­oc­u­lat­ing chil­dren and adults.

Any of the hun­dreds of thou­sands of kids and adults who were vac­ci­nat­ed with Deng­vax­ia who had not al­ready been in­fect­ed by one of the four dif­fer­ent serotypes of the virus faced a po­ten­tial­ly life-threat­en­ing fever if they went on to be in­fect­ed. Their bod­ies would like­ly treat the first re­al dengue in­fec­tion as their sec­ond, in light of the vac­cine. And sec­ond in­fec­tions are of­ten the most se­vere.

The DOH then sus­pend­ed the vac­ci­na­tion cam­paign as a na­tion­wide con­tro­ver­sy erupt­ed, trig­ger­ing head­lines through­out the coun­try. For­mer DOH un­der­sec­re­tary Su­san Pine­da Mer­ca­do ripped health of­fi­cials and Sanofi for ex­pos­ing peo­ple to a se­vere in­fec­tion. On her Face­book page, she wrote:

This is the biggest gov­ern­ment fund­ed clin­i­cal-tri­al-masked-as-a-pub­lic-health-pro­gram scam of an ex­per­i­men­tal drug in the his­to­ry of the DOH. And it cost the Philip­pines P3 B (3 bil­lion pe­sos, or about $70 mil­lion) for the vac­cines and so much more now for the risks, anx­i­ety and even lives that are now en­dan­gered. This was reck­less and ir­re­spon­si­ble from the start and the pub­lic was de­ceived in­to think­ing this vac­cine would pro­tect chil­dren from dengue.

On Sun­day, the Philip­pine gov­ern­ment re­spond­ed to the up­roar, vow­ing to get to the bot­tom of who was re­spon­si­ble for it.

“We will leave no stone un­turned in mak­ing those re­spon­si­ble for this shame­less pub­lic health scam which puts hun­dreds of thou­sands of young lives at risk ac­count­able,” said Har­ry Roque, the chief spokesper­son for Pres­i­dent Ro­dri­go Duterte, in a state­ment.

For its part, the WHO launched an emer­gency probe of the vac­cine on Mon­day, warn­ing coun­tries against in­ject­ing any­one who hadn’t been in­fect­ed ear­li­er.

Why are sec­ond in­fec­tions worse?

In the first dengue in­fec­tion, peo­ple typ­i­cal­ly get mild flu-like symp­toms as their body gen­er­ates an­ti­bod­ies that fight off the virus, which the vac­cine is al­so de­signed to kick up. Close to two years ago, Scott Hal­stead and Philip Rus­sell — both lead­ing fig­ures in the dengue field — point­ed to those an­ti­bod­ies as a se­vere threat to any­one who then is ex­posed to wild type dengue for the first time. At that point they as­sist the virus in a process called an­ti­body-de­pen­dent en­hance­ment, or ADE. And the most se­vere cas­es can lead to in­ter­nal bleed­ing, a res­pi­ra­to­ry cri­sis, or­gan fail­ure and death.

For peo­ple who had al­ready been in­fect­ed, the vac­cine could prove ex­tra­or­di­nar­i­ly help­ful, get­ting them past the risk of a sec­ond in­fec­tion and on to low­er-risk third or fourth in­fec­tions. But for any virus-naïve pa­tients, in­clud­ing the un­ex­posed chil­dren it was used on in the Philip­pines, it could be a dis­as­ter.

The threat Deng­vax­ia pos­es was al­so spot­light­ed in a ma­jor study pub­lished in Sci­ence just a few weeks af­ter the Philip­pines got busy vac­ci­nat­ing peo­ple. And the re­searchers, in­clud­ing Neil Fer­gu­son, di­rec­tor of the MRC Cen­ter for Out­break Analy­sis and Mod­el­ing at Im­pe­r­i­al Col­lege Lon­don, of­fered some wide­ly dis­cussed, stark warn­ings of ADE.

Derek Cum­mings

“You’d have in­creas­es in hos­pi­tal­ized dengue cas­es,” co-au­thor Derek Cum­mings, a pro­fes­sor at the Uni­ver­si­ty of Flori­da, told CNN last fall. “It would be ex­act­ly the op­po­site of what you in­tend to do.”

The au­thors un­der­scored that the vac­cine should be used on­ly in ar­eas where dengue is en­dem­ic, which is what the Philip­pines was do­ing.

The most ef­fec­tive so­lu­tion to elim­i­nat­ing the risk, Cum­mings and his col­leagues pro­posed, would be to de­vel­op a sim­ple test to see who had been ex­posed so they could ex­clude any­one who would be left vul­ner­a­ble to a sec­ond at­tack. And in­stead of the three dos­es rec­om­mend­ed by Sanofi for each sub­ject, you could prob­a­bly get the best ef­fect with one dose.

“I do not be­lieve … any­body should be go­ing for­ward us­ing this vac­cine with­out test­ing the in­di­vid­ual re­cip­i­ent to be sure they’re al­ready seropos­i­tive. Be­cause that’s the group that can ben­e­fit from this vac­cine,” Hal­stead, founder of the Chil­dren’s Vac­cine Ini­tia­tive, told STAT at the time the Sci­ence re­port came out.

And he had good rea­son to.

In Feb­ru­ary, 2016, be­fore the Philip­pine cam­paign be­gan, Hal­stead and Rus­sell, for­mer di­rec­tor of the Wal­ter Reed Army In­sti­tute of Re­search, pub­lished a piece in Vac­cine in which they drew a di­rect line be­tween the vac­cine and the ex­tra­or­di­nary like­li­hood it would trig­ger hos­pi­tal­iza­tions in a sub­se­quent wild type out­break. The threat grows as time pass­es be­tween in­fec­tions, they said, cit­ing a Cuban case from 1975 and a sub­se­quent 1995 epi­dem­ic — leav­ing any of the un­ex­posed chil­dren who were vac­ci­nat­ed at risk for the rest of their lives. And Hal­stead spot­ted the is­sue in Sanofi’s own da­ta, just as Cum­mings and his col­leagues did.

In a re­port by The Cen­ter for In­fec­tious Dis­ease Re­search and Pol­i­cy at the Uni­ver­si­ty of Min­neso­ta, Hal­stead says:

It’s clear as the nose on my face: Vac­cine re­cip­i­ents less than 5 years old had five to sev­en times more rates of hos­pi­tal­iza­tions for se­vere dengue virus than place­bo con­trols.

“What the com­pa­ny has done is say, ‘Well, we on­ly vac­ci­nate kids over the age 9,’ ” said Rus­sell in the CIDRAP re­port. “But age is on­ly a sur­ro­gate here for be­ing dengue naïve. They need to di­rect­ly ad­dress ADE in Phase IV stud­ies.”

Last April, Malaysian au­thor­i­ties de­mand­ed a Phase IV study be­fore al­low­ing a vac­ci­na­tion cam­paign, specif­i­cal­ly cit­ing the threat posed by a post-vac­ci­na­tion case of se­vere in­fec­tion.

“It was de­signed to fail”

Hal­stead tells me his dis­cov­ery of ADE in his lab dates back 60 years.

“This is a group of virus­es that evolved in mon­keys,” Hal­stead tells me, but sep­a­rat­ed in­to 4 dis­tinct virus­es over time. The first ex­po­sure makes an­ti­bod­ies against the dengue in­fec­tion, but those same an­ti­bod­ies in­ter­act dif­fer­ent­ly when they sub­se­quent­ly en­counter any of the oth­er three virus­es — not in a way that kills the virus. In­stead, they ef­fec­tive­ly dis­arm the im­mune sys­tem while spurring the growth of the virus.

“Just that at­tach­ment of that im­mune com­plex is suf­fi­cient to send a sig­nal to the root of the re­cep­tor that be­gins a process of switch­ing off the macrophages in the im­mune de­fense sys­tem,” he says.

In 1963, Scott Hal­stead was liv­ing in Thai­land and study­ing dengue and chikun­gun­ya in chil­dren. Scott Hal­stead

Click on the im­age to see the full-sized ver­sion


In new­borns to moth­ers who have had first ex­po­sures, he adds, you can see how the ba­bies with their trans­ferred im­mune re­sponse sud­den­ly de­vel­op the most se­vere, lethal re­ac­tion to dengue.

Those chil­dren who were seroneg­a­tive at the time they were vac­ci­nat­ed “are run­ning around now with this en­hanc­ing an­ti­body that they can’t get rid of,” says the sci­en­tist. “They can’t get rid of it for the rest of their lives.”

From Hal­stead’s per­spec­tive, there are two main cul­prits: Sanofi for de­vel­op­ing and mar­ket­ing the vac­cine with­out gain­ing a ba­sic un­der­stand­ing of the bi­ol­o­gy of dengue, and the WHO for val­i­dat­ing their con­clu­sions.

“It was de­signed to fail,” says Hal­stead about the vac­cine. “It doesn’t have the abil­i­ty to pro­duce strong T cell re­spons­es.” But he’s hope­ful that an­oth­er vac­cine in de­vel­op­ment at the NIH can do just that, and fix the prob­lem Sanofi cre­at­ed. In the mean­time, he says, Sanofi needs to step in and iden­ti­fy which chil­dren were left at risk, so they can be the first to be vac­ci­nat­ed with some­thing that does work.

Sanofi ex­ecs knew full well about the Sci­ence study, and shrugged it off at the time.

Ce­sar Mas­careñas

In an in­ter­view with Fier­cePhar­ma a few days af­ter the study came out, Ce­sar Mas­careñas, Sanofi Pas­teur’s di­rec­tor of glob­al med­ical af­fairs for dengue, dis­count­ed the re­port. That study, he re­port­ed­ly said, was a:

…“math­e­mat­i­cal mod­el” and not “ev­i­dence-based.” Plus, he said, it was one of 8 mod­els con­sid­ered by the WHO in mak­ing its rec­om­men­da­tion that the vac­cine be used in coun­tries where the virus is more than 50% preva­lent.

“It’s not new in­for­ma­tion for the ex­perts,” he said. “It has been tak­en in­to ac­count by the ex­perts at the WHO.”

A few months lat­er, in ear­ly Jan­u­ary, gov­ern­ment reg­u­la­tors cit­ed Sanofi for ig­nor­ing warn­ings that it was vi­o­lat­ing Philip­pine law by pro­mot­ing Deng­vax­ia to the gen­er­al pub­lic through TV and ra­dio ads.

“Since Sanofi has not com­plied, we have is­sued sum­mons di­rect­ing them to cease and de­sist from air­ing the ad­ver­tise­ments and Show Cause why they should not be pe­nal­ized for vi­o­lat­ing the law,” FDA di­rec­tor Gen­er­al Nela Cha­rade Puno said.

By last Wednes­day, Sanofi had a set of longterm da­ta to look at. And they con­clud­ed from it that the risks high­light­ed by the ear­li­er stud­ies was re­al.

For those not pre­vi­ous­ly in­fect­ed by dengue virus…the analy­sis found that in the longer term, more cas­es of se­vere dis­ease could oc­cur fol­low­ing vac­ci­na­tion up­on a sub­se­quent dengue in­fec­tion.

And the phar­ma com­pa­ny sug­gest­ed a la­bel change, ask­ing health­care of­fi­cials to de­ter­mine the “like­li­hood” of whether or not some­one had been pre­vi­ous­ly in­fect­ed be­fore pro­vid­ing the vac­ci­na­tion.

Sanofi’s re­sponse: “ADE can­not be the whole sto­ry”

The bulk of the in­for­ma­tion for this sto­ry was eas­i­ly gleaned from a short pe­ri­od of Googling. For a com­pa­ny that took 20 years and spent $1.6 bil­lion in de­vel­op­ment, prid­ing it­self on keep­ing close con­tact with KOLs and ex­perts in their field, it couldn’t be any kind of sur­prise. So I asked Sanofi what took them so long to an­nounce a con­clu­sion oth­ers had reached be­fore the big vac­ci­na­tion cam­paigns had even be­gun, lay­ing the foun­da­tion for the botched roll­out that ex­posed kids to the risk of se­vere dengue.

A spokesman for Sanofi, Lau­rence Bol­lack, replied by dis­put­ing the spe­cif­ic con­cern about ADE, not­ing that “ADE is one hy­poth­e­sis pro­posed to ex­plain this as­pect of dengue in­fec­tion but peo­ple can get se­vere­ly ill al­so at the first, third and fourth in­fec­tion with dengue so ADE can­not be the whole sto­ry. Rather se­vere dengue is like­ly mul­ti­fac­to­r­i­al due to fac­tors re­lat­ing to both the virus and per­son in­fect­ed.”

She al­so stat­ed:

“The new study that we con­duct­ed was not de­signed to prove nor dis­prove the ADE hy­poth­e­sis but rather to fur­ther eval­u­ate the per­for­mance of vac­ci­na­tion in two sub­groups of the orig­i­nal study pop­u­la­tion: those with and those with­out a pri­or dengue in­fec­tion be­fore vac­ci­na­tion.”

“(S)evere dengue is rare – about 0.5% or 1 in every 800 dengue cas­es,” added Bol­lack.

I asked if Sanofi is re­spon­si­ble to the chil­dren and adults who were un­ex­posed at the time they were vac­ci­nat­ed. Bol­lack said sub­jects of vac­ci­na­tion will con­tin­ue to be mon­i­tored, adding:

The ad­vice for vac­ci­nat­ed peo­ple is the same as for all peo­ple liv­ing in an en­dem­ic set­ting is to con­tin­ue to pro­tect against mos­qui­to bites and to seek med­ical care im­me­di­ate­ly if they ex­pe­ri­ence signs or symp­toms of dengue whether they have re­ceived the vac­cine or not.

Why not de­vel­op a test that can de­ter­mine pri­or ex­po­sure?

Sanofi in­tends to do that now, she says, but adds that there are a va­ri­ety of ways of de­ter­min­ing a pri­or in­fec­tion, in­clud­ing “doc­u­men­ta­tion of dengue in a pa­tient’s med­ical records, and al­so con­sid­er­ing avail­able epi­demi­o­log­i­cal da­ta on sero­preva­lence/dengue dis­ease bur­den in their com­mu­ni­ty.”

By ear­ly Oc­to­ber, 2016, long af­ter ex­pert warn­ings had been sound­ed in dengue cir­cles and be­yond, Deng­vax­ia had been ap­proved in 11 coun­tries, with the sup­port of the WHO. Sanofi’s lofty sales goals, though, ran straight in­to trou­ble. Last year, it brought in on­ly €55 mil­lion. And this year, the take was down to €22 mil­lion in the first 9 months. Third quar­ter sales reg­is­tered at a mi­nus­cule €4 mil­lion.

Sanofi, which has strug­gled to pro­duce any ma­jor new ther­a­pies in-house, topped that with a €100 mil­lion write-off for the pro­gram, just a frac­tion of their in­vest­ment so far. The com­pa­ny’s pri­ma­ry con­cern now is man­ag­ing a con­tro­ver­sy that is spread­ing around the world.

Like a virus.

Cell and Gene Con­tract Man­u­fac­tur­ers Must Em­brace Dig­i­ti­za­tion

The Cell and Gene Industry is growing at a staggering 30% CAGR and is estimated to reach $14B by 20251. A number of cell, gene and stem cell therapy sponsors currently have novel drug substances and products and many rely on Contract Development Manufacturing Organizations (CDMO) to produce them with adherence to stringent regulatory cGMP conditions. Cell and gene manufacturing for both autologous (one to one) and allogenic (one to many) treatments face difficult issues such as: a complex supply chain, variability on patient and cellular level, cell expansion count and a tight scheduling of lot disposition process. This complexity affects quality, compliance and accountability in the entire vein-to-vein process for critically ill patients.

A lab technician works during research on coronavirus at Johnson & Johnson subsidiary Janssen Pharmaceutical in Beerse, Belgium, Wednesday, June 17, 2020. (Virginia Mayo/AP Images)

End­points News ranks all 28 play­ers in the Covid-19 vac­cine race. Here's how it stacks up to­day

The 28 players now in or close to the clinical race to get a Covid-19 vaccine over the finish line are angling for a piece of a multibillion-dollar market. And being first — or among the leaders — will play a big role in determining just how big a piece.

Endpoints News writer Nicole DeFeudis has posted a snapshot of all the companies, universities and hospital-based groups now racing through the clinic, ranking them according to their place in the pipeline as well as the latest remarks available on timelines. And we’ll keep this lineup updated right through the end of the year, as the checkered flags start to fall, possibly as early as October.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 87,200+ biopharma pros reading Endpoints daily — and it's free.

Phase III read­outs spell dis­as­ter for Genen­tech’s lead IBD drug

Roche had big plans for etrolizumab. Eyeing a hyper-competitive IBD and Crohn’s market where they have not historically been a player, the company rolled out 8 different Phase III trials, testing the antibody for two different uses across a range of different patient groups.

On Monday, Roche released results for 4 of those studies, and they mark a decided setback for both the Swiss pharma and their biotech sub Genentech, potentially spelling an end to a drug they put over half-a-decade and millions of dollars behind.

Bayer's Marianne De Backer with Endpoints founder John Carroll, Endpoints@JPM20 (Jeff Rumans for Endpoints News)

UP­DAT­ED: Hunt­ing a block­buster, Bay­er forges an $875M-plus M&A deal to ac­quire women’s health biotech

Bayer has dropped $425 million in cash on its latest women’s health bet, bringing a UK biotech and its non-hormonal menopause treatment into the fold.

KaNDy Therapeutics had its roots in GlaxoSmithKline, which spun out several neuroscience drugs into NeRRe Therapeutics back in 2012. Five years later the team created a new biotech to focus solely on NT-814 — which they considered “one of the few true innovations in women’s health in more than two decades.”

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 87,200+ biopharma pros reading Endpoints daily — and it's free.

Eric Shaff (Seres)

UP­DAT­ED: Af­ter a 4-year so­journ, strug­gling mi­cro­bio­me pi­o­neer Seres claims a break­out PhI­II come­back. And shares re­spond in fren­zied spike

Almost exactly 4 years ago, Seres Therapeutics $MCRB experienced one of those soul-crunching failures that can raise big questions about a biotech’s future. Out front in their pursuit of a gut punch to C. difficile infection (CDI), the Phase II test was a flat failure, and investors wiped out a billion dollars of equity value that never returned in the years that followed.

Seres, though, pressed ahead, changing out CEOs a year ago — bidding Merck vet Roger Pomerantz farewell from the C suite — and pushing through a Phase III, hoping that amping up the dosage would make the key difference. And this morning, they unveiled a claim that they had aced the Phase III and positioned themselves for a run at a landmark FDA OK.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 87,200+ biopharma pros reading Endpoints daily — and it's free.

Michel Vounatsos, Biogen CEO (via YouTube)

Bio­gen scores a pri­or­i­ty re­view for its Alzheimer's drug ad­u­canum­ab, mov­ing one gi­ant leap for­ward in its con­tro­ver­sial quest

Biogen scored a big win at the FDA today as regulators accepted their application for the controversial Alzheimer’s drug aducanumab and gave it a priority review.

The PDUFA date is March 7, 2021.

Significantly, Biogen says it did not use its priority review voucher to win special treatment at the FDA. The agency handed that out gratis.

That’s the ideal scenario Biogen was looking for as disappointed analysts wondered aloud about the delayed application earlier in the year.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 87,200+ biopharma pros reading Endpoints daily — and it's free.

Robert Gould, Fulcrum Therapeutics CEO

Ful­crum stum­bles in PhII of old GSK drug, send­ing shares tum­bling

Investors are selling off shares of Fulcrum Therapeutics $FULC after their lead drug failed in a Phase II trial.

The company, founded three years ago on new research techniques such as CRISPR screening, isolated a gene called DUX4 they believed to have a central role in facioscapulohumeral muscular dystrophy, where patients’ muscle dies and is replaced by fat. And to target it, they licensed a GlaxoSmithKline drug that had failed as a cardio drug.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 87,200+ biopharma pros reading Endpoints daily — and it's free.

Eisai moves to 200 Metro Blvd. by late 2021 (ON3)

Ei­sai is cre­at­ing a new US cor­po­rate, R&D HQ in Roche’s old Nut­ley, NJ cam­pus

Eight years after Roche pulled up stakes from Nutley, NJ in a major R&D reorganization, Japan’s Eisai is moving its US corporate and research hub into their old campus.

Now the ON3 property, Eisai — a longtime Biogen partner focused on neurodegenerative disorders like Alzheimer’s — will bring together a staff of up to 1,200 employees. And execs are pitching the move to the New Jersey campus as a cultural game-changer.

Lig­and scoops up Pfenex for up to $516M, adding pro­teins to their an­ti­body chick­ens and de­liv­ery tech

The technology hunting folks over at Ligand Pharmaceuticals have picked up a new one from across town, for a significant price.

Ligand has acquired fellow San Diego-based biotech Pfenex and their protein expression platform for $438 million cash, plus $78 million in contingent value agreements should an undisclosed milestone be hit before the end of next year.  The deal pays $12 per share, or $4.34 more than what Pfenex had been trading at before the announcement.