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.

De­vel­op­ment of the Next Gen­er­a­tion NKG2D CAR T-cell Man­u­fac­tur­ing Process

Celyad’s view on developing and delivering a CAR T-cell therapy with multi-tumor specificity combined with cell manufacturing success
Overview
Transitioning potential therapeutic assets from academia into the commercial environment is an exercise that is largely underappreciated by stakeholders, except for drug developers themselves. The promise of preclinical or early clinical results drives enthusiasm, but the pragmatic delivery of a therapy outside of small, local testing is most often a major challenge for drug developers especially, including among other things, the manufacturing challenges that surround the production of just-in-time and personalized autologous cell therapy products.

Paul Hudson. Sanofi

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When Paul Hudson lays out his R&D vision for Sanofi tomorrow, he will have a new slate of interleukin therapies and a synthetic biology platform to boast about.

The French pharma giant announced early Monday that it is snagging San Diego biotech Synthorx in a $2.5 billion deal. That marks an affordable bolt-on for Sanofi but a considerable return for Synthorx backers, including Avalon, RA Capital and OrbiMed: At $68 per share, the price represents a 172% premium to Friday’s closing.

Synthorx’s take on alternative IL-2 drugs for both cancer and autoimmune disorders — enabled by a synthetic DNA base pair pioneered by Scripps professor Floyd Romesberg — “fits perfectly” with the kind of innovation that he wants at Sanofi, Hudson said.

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#ASH19: Here’s why Mer­ck is pay­ing $2.7B to­day to grab Ar­Qule and its next-gen BTK drug, lin­ing up Eli Lil­ly ri­val­ry

Just a few months after making a splash at the European Hematology Association scientific confab with an early snapshot of positive data for their BTK inhibitor ARQ 531, ArQule has won a $2.7 billion buyout deal from Merck.

Merck is scooping up a next-gen BTK drug — which is making a splash at ASH today — from ArQule in an M&A pact set at $20 a share $ARQL. That’s more than twice Friday’s $9.66 close. And Merck R&D chief Roger Perlmutter heralded a deal that nets “multiple clinical-stage oral kinase inhibitors.”

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Ob­sE­va makes case for best-in-class hor­mone sup­pres­sive ther­a­py in pos­i­tive uter­ine fi­broid study

About a month after the Swiss biotech disclosed a failed late-stage study in its IVF program, ObsEva on Monday unveiled positive pivotal data on its experimental treatment for heavy menstrual bleeding triggered by uterine fibroids.

ObsEva in-licensed the drug, linzagolix, from Japan’s Kissei Pharmaceutical in 2015. Two doses of the drug (100 mg and 200 mg) were tested against a placebo in the 535-patient Phase III study, dubbed PRIMROSE 2, in patients who were both on and off hormonal add-back therapy (ABT).

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Bristol-Myers Squibb came to ASH this past weekend with a variety of messages on the new cancer drugs they had acquired in the big Celgene buyout, including liso-cel, the lead CAR-T program picked up in the $9 billion Juno acquisition. And one of the most important was that they had the pivotal efficacy and safety data needed to snag an approval from the FDA next year, with the BLA on track for a filing this month.

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Just hours after J&J’s oncology team bragged about scoring a breakthrough therapy designation for their BCMA CAR-T drug, they pulled the wraps off of the multiple myeloma data for JNJ-4528 that impressed the FDA. And it’s easy to see why they may well be on a short path to a landmark approval — which may well be making the rival team at bluebird/Bristol-Myers more than a little nervous.

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J&J's Mathai Mammen at an Endpoints News event in Boston, June 2018 (Photo: Rob Tannenbaum for Endpoints News)

J&J fronts $750M cash to grab a failed can­cer drug that’s been re­pur­posed as a pow­er­ful an­ti-in­flam­ma­to­ry

J&J has stepped up with one of its blockbuster drug buys, agreeing to pay Austin-based XBiotech $XBIT $750 million in cash and up to $600 million more in milestones for their late stage-ready anti-inflammatory drug bermekimab — which some longtime biotech observers may recognize as a failed cancer therapy with a disaster-prone past.

The drug targets the IL-1a pathway. J&J $JNJ R&D chief Mathai Mammen is cutting a check for a drug that has produced positive mid-stage data in patients suffering from a skin condition called hidradenitis suppurativa with another mid-stage program underway for atopic dermatitis.

That puts J&J in charge of a drug on the threshold of pivotal — though pricey — R&D work for a broad patient group with other related fields to explore. And it’s a very busy development arena.

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Jake Van Naarden, Josh Bilenker, Nisha Nanda (Credit: Loxo, Aisling Capital)

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So what are they doing?

They formed a new executive team that is taking over the management of Eli Lilly’s hundreds-strong oncology R&D group — essentially using Loxo as a base for a bold new experiment in Big Pharma R&D in an attempt to create a true biotech environment with the deep pockets of a top-15 industry player. They’ve recruited David Hyman from Memorial Sloan Kettering to join the team as chief medical officer. And the mandate includes culling out the oncology pipeline, highlighting their star prospects and going after new programs wherever they can find the best prospects.

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Patient number 9 has given Sangamo and its partners at Pfizer some heart palpitations in their high profile hemophilia A gene therapy program.

After watching his Factor VIII level rise following treatment like the rest, the crucial efficacy gauge they track saw a sudden and significant plunge. At week 13, the FVIII level had dropped below normal. Then it began to rise again.

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