Roche's Xofluza may give rise to re­sis­tant strains, rais­ing fears of a 'worst case sce­nar­i­o'

In 2018, Sh­iono­gi rolled out Xofluza in Japan as a one-dose kill for in­fluen­za, with Roche fol­low­ing suit in the US. Soon, though, Japan­ese reg­u­la­tors no­ticed the drug was lead­ing to re­sis­tant flu strains, and now a new study in Na­ture con­firms the drug leads to spe­cif­ic mu­ta­tions that may ham­per its promise to neu­tral­ize the virus in a sin­gle dose.

An­drew Pekosz John Hop­kins

“In a worst case sce­nario, these mu­ta­tions could ren­der the drug en­tire­ly use­less,” An­drew Pekosz, a mol­e­c­u­lar bi­ol­o­gist at Johns Hop­kins who was not in­volved in the study, told End­points News. “They haven’t yet, and it’s not clear why that’s been the case.”

No­tably, Pekosz said, the mu­tant virus­es have not spread ex­ten­sive­ly in hu­mans. Rather, re­searchers at the Uni­ver­si­ty of Wis­con­sin and the Uni­ver­si­ty of Tokyo took strains from pa­tients in Japan who had re­ceived Xofluza and found some con­tained mu­ta­tions to a struc­ture the virus us­es to repli­cate it­self, called the poly­merase com­plex.

Xofluza, or balox­avir acid, tar­gets this com­plex to kill the virus. When re­searchers test­ed the mu­tant strains in an­i­mal and cell lines, they found it was re­sis­tant to the drug and ca­pa­ble of spread­ing. Of 77 sam­pled chil­dren, 18 (23%) had mu­tant strains.

“This is not the first study, maybe one of the most ex­ten­sive ones, that show a sin­gle mu­ta­tion can cause re­sis­tance,” Pekosz said. “And those re­sis­tant virus­es still seem to have the abil­i­ty to repli­cate and spread just like the wild virus.”

Roche billed Xofluza as the first flu treat­ment ap­proved in 20 years and tout­ed the com­pli­ance ad­van­tages over its pre­de­ces­sor Tam­i­flu; One dose on one day as op­posed to 10 dos­es over 5 days. But re­sis­tance has been a con­tin­u­al prob­lem with such drugs. Most no­tably, the once-com­mon flu drug aman­ta­dine is no longer pre­scribed as vir­tu­al­ly all strains have be­come re­sis­tant.

As Xofluza neared ap­proval, re­searchers warned it may cause re­sis­tance. A New Eng­land Jour­nal of Med­i­cine ed­i­to­r­i­al pub­lished a month be­fore the drug’s US ap­proval found treat­ment led to “the emer­gence of vi­ral es­cape mu­tants with re­duced sus­cep­ti­bil­i­ty.”

“The is­sue for pub­lic health is whether these in­fluen­za virus­es with re­duced sus­cep­ti­bil­i­ty to balox­avir are trans­mis­si­ble,” wrote Tim­o­thy M. Uye­ki.

That ques­tion re­mains in­con­clu­sive, al­though the au­thors of the Na­ture study not­ed that one child who had not re­ceived Xofluza nev­er­the­less test­ed pos­i­tive for a re­sis­tant strain, “sug­gest­ing the pos­si­bil­i­ty of per­son-to-per­son trans­mis­sion of the vari­ant.”

For Pekosz, the ques­tions un­der­score the need for flu drug cock­tails that at­tack the virus from mul­ti­ple an­gles, like how doc­tors treat the HIV; If a virus needs two pre­cise mu­ta­tions to sur­vive and evolve, it’s much more less like­ly to.

“We’re mak­ing it too easy for the virus to es­cape,” he said.

Fangliang Zhang, AP Images

UP­DAT­ED: Leg­end fetch­es $424 mil­lion, emerges as biggest win­ner yet in pan­dem­ic IPO boom as shares soar

Amid a flurry of splashy pandemic IPOs, a J&J-partnered Chinese biotech has emerged with one of the largest public raises in biotech history.

Legend Biotech, the Nanjing-based CAR-T developer, has raised $424 million on NASDAQ. The biotech had originally filed for a still-hefty $350 million, based on a range of $18-$20, but managed to fetch $23 per share, allowing them to well-eclipse the massive raises from companies like Allogene, Juno, Galapagos, though they’ll still fall a few dollars short of Moderna’s record-setting $600 million raise from 2018.

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As it hap­pened: A bid­ding war for an an­tibi­ot­ic mak­er in a mar­ket that has rav­aged its peers

In a bewildering twist to the long-suffering market for antibiotics — there has actually been a bidding war for an antibiotic company: Tetraphase.

It all started back in March, when the maker of Xerava (an FDA approved therapy for complicated intra-abdominal infections) said it had received an offer from AcelRx for an all-stock deal valued at $14.4 million.

The offer was well-timed. Xerava was approved in 2018, four years after Tetraphase posted its first batch of pivotal trial data, and sales were nowhere near where they needed to be in order for the company to keep its head above water.

Is a pow­er­house Mer­ck team prepar­ing to leap past Roche — and leave Gilead and Bris­tol My­ers be­hind — in the race to TIG­IT dom­i­na­tion?

Roche caused quite a stir at ASCO with its first look at some positive — but not so impressive — data for their combination of Tecentriq with their anti-TIGIT drug tiragolumab. But some analysts believe that Merck is positioned to make a bid — soon — for the lead in the race to a second-wave combo immuno-oncology approach with its own ambitious early-stage program tied to a dominant Keytruda.

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Bris­tol My­ers is clean­ing up the post-Cel­gene merg­er pipeline, and they’re sweep­ing out an ex­per­i­men­tal check­point in the process

Back during the lead up to the $74 billion buyout of Celgene, the big biotech’s leadership did a little housecleaning with a major pact it had forged with Jounce. Out went the $2.6 billion deal and a collaboration on ICOS and PD-1.

Celgene, though, also added a $530 million deal — $50 million up front — to get the worldwide rights to JTX-8064, a drug that targets the LILRB2 receptor on macrophages.

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Leen Kawas, Athira CEO (Athira)

Can a small biotech suc­cess­ful­ly tack­le an Ever­est climb like Alzheimer’s? Athi­ra has $85M and some in­flu­en­tial back­ers ready to give it a shot

There haven’t been a lot of big venture rounds for biotech companies looking to run a Phase II study in Alzheimer’s.

The field has been a disaster over the past decade. Amyloid didn’t pan out as a target — going down in a litany of Phase III failures — and is now making its last stand at Biogen. Tau is a comer, but when you look around and all you see is destruction, the idea of backing a startup trying to find complex cocktails to swing the course of this devilishly complicated memory-wasting disease would daunt the pluckiest investors.

GSK presents case to ex­pand use of its lu­pus drug in pa­tients with kid­ney dis­ease, but the field is evolv­ing. How long will the mo­nop­oly last?

In 2011, GlaxoSmithKline’s Benlysta became the first biologic to win approval for lupus patients. Nine years on, the British drugmaker has unveiled detailed positive results from a study testing the drug in lupus patients with associated kidney disease — a post-marketing requirement from the initial FDA approval.

Lupus is a drug developer’s nightmare. In the last six decades, there has been just one FDA approval (Benlysta), with the field resembling a graveyard in recent years with a string of failures including UCB and Biogen’s late-stage flop, as well as defeats in Xencor and Sanofi’s programs. One of the main reasons the success has eluded researchers is because lupus, akin to cancer, is not just one disease — it really is a disease of many diseases, noted Al Roy, executive director of Lupus Clinical Investigators Network, an initiative of New York-based Lupus Research Alliance that claims it is the world’s leading private funder of lupus research, in an interview.

Drug man­u­fac­tur­ing gi­ant Lon­za taps Roche/phar­ma ‘rein­ven­tion’ vet as its new CEO

Lonza chairman Albert Baehny took his time headhunting a new CEO for the company, making it absolutely clear he wanted a Big Pharma or biotech CEO with a good long track record in the business for the top spot. In the end, he went with the gold standard, turning to Roche’s ranks to recruit Pierre-Alain Ruffieux for the job.

Ruffieux, a member of the pharma leadership team at Roche, spent close to 5 years at the company. But like a small army of manufacturing execs, he gained much of his experience at the other Big Pharma in Basel, remaining at Novartis for 12 years before expanding his horizons.

Covid-19 roundup: Ab­b­Vie jumps in­to Covid-19 an­ti­body hunt; As­traZeneca shoots for 2B dos­es of Ox­ford vac­cine — with $750M from CEPI, Gavi

Another Big Pharma is entering the Covid-19 antibody hunt.

AbbVie has announced a collaboration with the Netherlands’ Utrecht University and Erasmus Medical Center and the Chinese-Dutch biotech Harbour Biomed to develop a neutralizing antibody that can treat Covid-19. The antibody, called 47D11, was discovered by AbbVie’s three partners, and AbbVie will support early preclinical work, while preparing for later preclinical and clinical development. Researchers described the antibody in Nature Communications last month.

Gilead bol­sters its case for block­buster hope­ful fil­go­tinib as FDA pon­ders its de­ci­sion

Before remdesivir soaked up the spotlight amid the coronavirus crisis, Gilead’s filgotinib was the star experimental drug tapped to rake in billions competing with other JAK inhibitors made by rivals including AbbVie and Eli Lilly.

Now, long term data on the drug — discovered by Gilead’s partners at Galapagos and posted as part of a virtual medical conference — have solidified the durability and safety of filgotinib in patients with rheumatoid arthritis, spanning data from three late-stage trials. An FDA decision on the drug is expected this year.