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.

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

No­vo CEO Lars Fruer­gaard Jør­gensen on R&D risk, the deal strat­e­gy and tar­gets for gen­der di­ver­si­ty

 

I kicked off our European R&D summit last week with a conversation involving Novo Nordisk CEO Lars Fruergaard Jørgensen. Novo is aiming to launch a new era of obesity management with a new approval for semaglutide. And Jørgensen had a lot to say about what comes next in R&D, how they manage risk and gender diversity targets at the trendsetting European pharma giant.

John Carroll: I’m here with Lars Jørgensen, the CEO of Novo Nordisk. Lars, it’s been a really interesting year so far with Novo Nordisk, right? You’ve projected a new era of growing sales. You’ve been able to expand on the GLP-1 franchise that was already well established in diabetes now going into obesity. And I think a tremendous number of people are really interested in how that’s working out. You have forecast a growing amount of sales. We don’t know specifically how that might play out. I know a lot of the analysts have different ideas, how those numbers might play out, but that we are in fact embarking on a new era for Novo Nordisk in terms of what the company’s capable of doing and what it’s able to do and what it wants to do. And I wanted to start off by asking you about obesity in particular. Semaglutide has been approved in the United States for obesity. It’s an area of R&D that’s been very troubled for decades. There have been weight loss drugs that have come along. They’ve attracted a lot of attention, but they haven’t actually ever gained traction in the market. My first question is what’s different this time about obesity? What is different about this drug and why do you expect it to work now whereas previous drugs haven’t?

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Sur­geons suc­cess­ful­ly at­tach pig kid­ney to a hu­man for the first time, us­ing tech from Unit­ed's Re­vivi­cor

In a first, researchers reportedly successfully transplanted a pig kidney into a human without triggering an immediate immune response this week. And the technology came from the biotech United Therapeutics.

Surgeons spent three days attaching the kidney to the patient’s blood vessels, but when all was said and done, the kidney appeared to be functioning normally in early testing, Reuters and the New York Times were among those to report. The kidney came from a genetically altered pig developed through United’s Revivicor unit.

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David Livingston (Credit: Michael Sazel for CeMM)

Renowned Dana-Far­ber sci­en­tist, men­tor and bio­phar­ma ad­vi­sor David Liv­ingston has died

David Livingston, the Dana-Farber/Harvard Med scientist who helped shine a light on some of the key molecular drivers of breast and ovarian cancer, died unexpectedly last Sunday.

One of the senior leaders at Dana-Farber during his nearly half century of work there, Livingston was credited with shedding light on the genes that regulate cell growth, with insights into inherited BRCA1 and BRCA2 mutations that helped lay the scientific foundation for targeted therapies and earlier detection that have transformed the field.

Man­u­fac­tur­ing woes for No­vavax’s Covid jab bad­ly dis­rupt plans for roll­out to the poor — re­port

Production problems at a Novavax facility in Maryland have led to delays in the Covax vaccine sharing program. Now, a shortage of 1 billion doses is expected, as the supplier tries to navigate producing a shot up to regulators’ standards, Politico reported Tuesday.

The company has run into trouble with the purity of the vaccine. Novavax has had trouble proving it can produce a shot consistently up to standards, and it has caused significant delays in the rollout to low- and middle-income countries. This follows several delays at Novavax that has put the executive crew on the defensive.

Break­ing: Bio­gen sells just $300K worth of Aduhelm in Q3, as ques­tions on long term vi­a­bil­i­ty re­main

Barely anyone is accessing Biogen’s controversial Alzheimer’s treatment, with the company reporting just $0.3 million in Aduhelm sales in the third quarter. Although investors will be looking to the longer term, when CMS may decide to cover the drug and open the floodgates for more coverage, use of the drug is currently stalled.

Since June, when the FDA first signed off on the drug under its accelerated pathway, Biogen said Wednesday that it’s sold a total of $2 million worth of Aduhelm. Biogen said on its earnings call that about 120 sites so far have infused at least one patient with Aduhelm, which is priced at $56,000 annually. Morgan Stanley previously predicted about 14,000 patients will access Aduhelm by the end of 2022.

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Bill Gates at the Global Investment Summit in London, Oct. 19, 2021 (Leon Neal/Pool via AP Images)

Gates Foun­da­tion pledges $120M to ramp up gener­ic sup­ply of Mer­ck­'s Covid-19 pill while ac­tivists blast Pfiz­er's dis­pro­por­tion­ate pow­er

Merck’s molnupiravir may not be officially authorized anywhere in the world yet, but who will get access to it has shaped up to be a huge issue. The Bill & Melinda Gates Foundation is now stepping up to ensure lower-income countries won’t be left behind — and calling on others to follow its lead.

The oral antiviral pill, which was shown to dramatically cut the risk of severe Covid-19 disease and death in a Phase III study, is the latest rallying symbol in the battle against not just the coronavirus but the inequality it’s exposed.

With hun­dreds of mil­lions spent on failed ac­cel­er­at­ed ap­provals, re­searchers call for faster FDA with­drawals

Between 2017 and 2019, Medicare spent more than $220 million on cancer drugs for which the indications were either voluntarily pulled by their applicants or FDA’s oncology adcomm had recommended their withdrawal.

That kind of massive spending on cancer drugs lacking overall survival benefit is wasteful and risks harming people’s health, a research letter published in JAMA Internal Medicine on Monday said. The researchers from Harvard and the London School of Economics called on the FDA to move faster in both requiring timely postmarketing trials and accelerating the speed in pulling these dangling approvals when the confirmatory studies fail.

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Bio­gen hit by ALS set­back with PhI­II fail­ure for tofersen — but fol­lows a fa­mil­iar strat­e­gy high­light­ing the pos­i­tive

Patients and analysts waiting to hear Sunday how Biogen’s SOD1-ALS drug tofersen fared in Phase III didn’t have to wait long for the top-line result they were all waiting for. The drug failed the primary endpoint on significantly improving the functional and neurologic decline of patients over 28 weeks as well as the extension period for continued observation.

In fact, there was very little difference in response.

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