With its dengue vac­cine in the reg­u­la­to­ry queue, Take­da out­lines longterm fol­lowup da­ta that it says keep it out of Deng­vax­i­a's shad­ow

When Sanofi pub­lished longterm fol­lowup re­sults from a trio of Phase III tri­als for its dengue vac­cine in 2015, in­ves­ti­ga­tors flagged a con­cern­ing ob­ser­va­tion that they weren’t able to ex­plain: In the third year post-vac­ci­na­tion, chil­dren younger than 9 who got the jabs were more like­ly to end up in the hos­pi­tal than those in the con­trol group.

The hos­pi­tal­iza­tion im­bal­ance didn’t stop Sanofi from clinch­ing the ap­proval to start the world’s first large-scale vac­ci­na­tion cam­paign in the Philip­pines with its vac­cine, Deng­vax­ia. But even though pub­lic health of­fi­cials tried to skirt it by lim­it­ing the in­oc­u­la­tion dri­ve to old­er chil­dren and adults, the is­sue — which Sanofi was lat­er ac­cused of play­ing down — would come back to haunt the ef­fort. Kids and adults were de­vel­oped with se­vere fever af­ter vac­cines, in some cas­es lethal, spark­ing na­tion­wide pan­ic and forc­ing the Phillip­pine gov­ern­ment to shut down the pro­gram. Even though Deng­vax­ia even­tu­al­ly got adopt­ed in oth­er coun­tries, the fi­as­co left its scars.

Take­da, which has been push­ing its own dengue vac­cine un­der that cloud for the past eight years, now has the three-year fol­lowup da­ta to sug­gest it can steer clear of that wreck­age — al­though some gaps re­main be­fore we get a com­plete pro­file of the shot.

With those re­sults now in, the Japan­ese phar­ma has al­so com­plet­ed the pack­age it needs to file with reg­u­la­tors. Take­da sub­mit­ted for a mar­ket­ing ap­proval with the EMA in March, and it’s plot­ting more in dengue-en­dem­ic coun­tries like Ar­genti­na, Brazil, Colom­bia, In­done­sia, Malaysia, Mex­i­co, Sin­ga­pore, Sri Lan­ka and Thai­land. An FDA fil­ing is ex­pect­ed to fol­low lat­er this year.

Derek Wal­lace

Hav­ing fol­lowed 20,000 study par­tic­i­pants for 36 months af­ter their sec­ond dose of TAK-003, in­ves­ti­ga­tors re­port­ed that vac­cine ef­fi­ca­cy against hos­pi­tal­ized dengue is 83.6%.

“That’s re­al­ly the com­po­nent of the ill­ness that has the most im­pact, at an in­di­vid­ual lev­el whether that’s on health or fi­nances, it’s al­so the as­pect of dengue that has the great­est im­pact on pub­lic health sys­tems and our com­mu­ni­ties,” Derek Wal­lace, the dengue pro­gram leader at Take­da, told End­points News in a pre­view.

The ef­fi­ca­cy num­bers are sim­i­lar re­gard­less of whether the vac­cine re­cip­i­ent has had a pre­vi­ous dengue in­fec­tion — 86% for the seropos­i­tive group and 77.1% for the seroneg­a­tive group — which is no­table be­cause a phe­nom­e­non known as an­ti­body-de­pen­dent en­hance­ment in virus-naïve pa­tients had been blamed for Deng­vax­ia’s prob­lems.

Over­all vac­cine ef­fi­ca­cy, as mea­sured by vi­ro­log­i­cal­ly-con­firmed dengue, reg­is­tered at 62.0%, with 65% in seropos­i­tive in­di­vid­u­als and 54.3% in seroneg­a­tive in­di­vid­u­als.

The pro­tec­tion that the vac­cine of­fers has waned across the board com­pared to the last cut of da­ta at 18 months, when Take­da tout­ed an over­all ef­fi­ca­cy rate of 73% and re­duc­tion of 90% in dengue-re­quired hos­pi­tal­iza­tion com­pared to place­bo. But the wan­ing fo­cused on what Wal­lace calls “am­bu­la­to­ry dengue” and the drop was small­er in the group that mat­tered.

But Take­da didn’t pro­vide an up­date on the break­down of ef­fi­ca­cy in each of four dengue serotypes, say­ing it will save those num­bers for pub­li­ca­tion in a peer-re­viewed jour­nal lat­er this year. At 18 months, while the ef­fi­ca­cy for dengue 1 and dengue 2 looked promis­ing, there were con­cerns about a lack of ef­fi­ca­cy for dengue 3. (For dengue 4, the da­ta were in­con­clu­sive.)

Sanofi scored ap­proval for Deng­vax­ia with Phase III da­ta that were pre­sent­ed in a slight­ly dif­fer­ent way, sug­gest­ing pooled rates of ef­fi­ca­cy for symp­to­matic dengue dur­ing the first 25 months of 60.3% — and pooled rel­a­tive risks of hos­pi­tal­iza­tion for dengue of 0.84.

Per the pro­to­col, Take­da will mon­i­tor the par­tic­i­pants for an­oth­er year and a half. Af­ter 4.5 years, it plans to test whether a boost­er would of­fer more pro­tec­tion in the long run.

“The world we live in now with Covid-19 has re­al­ly shown the po­ten­tial­ly dev­as­tat­ing im­pact that in­fec­tious dis­eases can have, and the val­ue of care­ful vac­cine de­vel­op­ments and im­ple­men­ta­tion of vac­cine pro­grams,” Wal­lace said. “In the back­ground of all that, we have dengue. Dengue has been around for decades be­fore Covid-19 and it will be around for decades to come. It’s a dis­ease that is mas­sive in its im­pact, af­fect­ing half of the world’s pop­u­la­tion and it’s not a dis­ease that we’ve got a very good han­dle on in terms of man­age­ment or pre­ven­tion.”

They’ve come a long way to ar­rive at a stage where they are prepar­ing to talk to reg­u­la­tors. Orig­i­nal­ly de­rived in the lab­o­ra­to­ries of Su­tee Yok­san at Mahi­dol Uni­ver­si­ty in Thai­land, the live-at­ten­u­at­ed vac­cine con­struct was mus­cled up at the US CDC and went through clin­i­cal stud­ies at In­vi­ra­gen be­fore Take­da snapped the biotech up in 2013, while the dengue pro­gram was still in Phase II, ac­cord­ing to a spokesper­son.

Covid-19, of course, still fig­ures promi­nent­ly in the minds of any vac­cine de­vel­op­er. Even as Take­da ham­mers out the arrange­ment for its Ger­man con­tract man­u­fac­tur­er IDT to make the ini­tial dos­es of TAK-003 should it be ap­proved (be­fore even­tu­al­ly set­ting up its own pro­duc­tion in Ger­many), it will be pro­vid­ing some man­u­fac­tur­ing slots there to make J&J’s coro­n­avirus vac­cine while help­ing Mod­er­na dis­trib­ute its shots in Japan.

Pi­o­neer­ing Click Chem­istry in Hu­mans

Reimagining cancer treatments

Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020, which is nearly one in six deaths. Recently, we have seen incredible advances in novel cancer therapies such as immune checkpoint inhibitors, cell therapies, and antibody-drug conjugates that have revamped cancer care and improved survival rates for patients.

Despite this significant progress in therapeutic targeting, why are we still seeing such a high mortality rate? The reason is that promising therapies are often limited by their therapeutic index, which is a measure of the effective dose of a drug, relative to its safety. If we could broaden the therapeutic indices of currently available medicines, it would revolutionize cancer treatments. We are still on the quest to find the ultimate cancer medicine – highly effective in several cancer types, safe, and precisely targeted to the tumor site.

Justin Klee (L) and Joshua Cohen, Amylyx co-CEOs (Cody O'Loughlin/The New York Times; courtesy Amylyx)

Ad­vo­cates, ex­perts cry foul over Amy­lyx's new ALS drug, cit­ing is­sues with price, PhI­II com­mit­ment

Not 24 hours after earning the first ALS drug approval in five years, Amylyx Pharmaceuticals’ Relyvrio is already drawing scrutiny. And it’s coming from multiple fronts.

In an investor call Friday morning, Amylyx revealed that it would charge about $158,000 per year, a price point that immediately drew backlash from ALS advocates and some outside observers. The cost reveal had been highly anticipated in the immediate hours after Thursday evening’s approval, though Amylyx only teased Relyvrio would cost less than previously approved drugs.

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Land­mark Amy­lyx OK spurs de­bate; Some... pos­i­tive? Alzheimer's da­ta; Can­cer tri­al bot­tle­neck; Sanofi's CRISPR bet; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

After brief stops in Paris and Boston, John Carroll and the Endpoints crew are staying on the road in October with their return for a live/streaming EUBIO22 in London. The hybrid event fireside chats and panels on mRNA, oncology and the crazy public market. We hope you can join him there.

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Joshua Cohen (L) and Justin Klee, Amylyx co-CEOs

Up­dat­ed: Af­ter long and wind­ing road, FDA ap­proves Amy­lyx's ALS drug in vic­to­ry for pa­tients and ad­vo­ca­cy groups

For just the third time in its 116-year history, the FDA has approved a new treatment for Lou Gehrig’s disease, or ALS.

US regulators gave the thumbs-up to the drug, known as Relyvrio, in a massive win for patients and their families. The approval, given to Boston-area biotech Amylyx Pharmaceuticals, comes after two years of long and contentious debates over the drug’s effectiveness between advocacy groups and FDA scientists, following the readout of a mid-stage clinical trial in September 2020.

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Up­dat­ed: Al­ny­lam re­in­forces APOL­LO-B patisir­an da­ta be­fore head­ing to the FDA

Weeks after uncorking some mostly positive data for patisiran in transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy, Alnylam is bolstering its package with new exploratory and subgroup data before shipping it off to regulators.

The RNAi drug maintained “generally consistent” benefits in efficacy and quality of life across several prespecified subgroups at month 12, Alnylam announced on Friday afternoon, including age, baseline tafamidis use, ATTR amyloidosis type, baseline six-minute walk test score and others.

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#AAO22: J&J’s first look at com­mon eye dis­ease port­fo­lio pads the case for PhII of gene ther­a­py

CHICAGO — While the later-stage drug developers in the geographic atrophy field are near the finish line, Johnson & Johnson’s Janssen is taking a more deliberate route, with a treatment that it hopes to be a one-time fix.

The Big Pharma will take its Hemera Biosciences-acquired gene therapy into a Phase II study later this year in patients with GA, a common form of age-related macular degeneration that impacts about five million people worldwide. To get there, Janssen touted early-stage safety data at the American Academy of Ophthalmology annual conference Saturday morning, half a day after competitors Apellis and Iveric Bio revealed their own more-detailed Phase III analyses.

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Jerome Durso, Intercept Pharmaceuticals CEO

In­ter­cep­t's OCA fails a PhI­II NASH tri­al, rais­ing fresh doubts about its years­long quest for an OK

Intercept Pharmaceuticals has run into another big setback in its yearslong quest to win an approval for OCA in NASH. The biotech put out word Friday morning that its Phase III REVERSE study failed the primary endpoint for the liver disease, sending its share price into a tailspin.

There was no significant improvement in fibrosis among the patients suffering from cirrhosis who were treated with obeticholic acid, with investigators hunting for a minimum 1-stage histological improvement in the disease after 18 months of therapy.

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#AAO22 conference in Chicago (Photo credit: Associate editor Kyle LaHucik)

#AAO22: Iver­ic Bio, un­de­terred by loom­ing PDU­FA for com­peti­tor, touts sub­group da­ta on GA drug

CHICAGO — While its competitor is on the cusp of likely securing the first FDA nod, Iveric Bio is trudging ahead with its potential treatment for geographic atrophy, an advanced form of AMD, and has new data to support its upcoming NDA filing.

The biotech said its drug was more favorable than sham across all subgroups in the second Phase III study of the investigational complement C5 protein inhibitor, performing similarly to a previous, smaller late-stage trial.

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#AAO22 conference in Chicago (Photo credit: Associate editor Kyle LaHucik)

#AAO22: In bid for first FDA nod in ge­o­graph­ic at­ro­phy, Apel­lis claims an­oth­er first in eye dis­ease field

CHICAGO — Eight weeks before patients and industry find out if the FDA approves the first treatment for geographic atrophy, an advanced form of age-related macular degeneration, the biotech behind the drug is out with some new data on a secondary endpoint.

In what study investigator Charles Wykoff called the “first direct evidence of function preservation by slowing GA growth” in an investigational treatment, Apellis Pharmaceuticals’ drug pegcetacoplan led to less loss of retinal sensitivity versus sham  within 250 microns on either side of the GA lesion over 24 months.

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