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Monday, August 2, 2021

Bristol Myers pulls lymphoma indication for Istodax after confirmatory trial falls flat

 Amid an industrywide review of cancer drugs with accelerated approval, Bristol Myers Squibb had to make the tough call last month to yank an approval for leading I/O drug Opdivo after flopping a confirmatory study. Now, a second Bristol Myers drug is on the chopping block.


Bristol Myers has pulled aging HDAC inhibitor Istodax’s indication in peripheral T cell lymphoma after a Phase III confirmatory study for the drug flopped on its progression-free survival endpoint, the drugmaker said Monday.


Istodax, a Celgene drug first approved way back in 2009, earned its accelerated approval in PTCL, a form of non-Hodgkin lymphoma, in 2011, but it took nearly a decade for the confirmatory results to gestate. At ASH 2020, Bristol Myers rolled out data showing Istodax couldn’t benefit clinical outcomes when added to a regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).


So late in its life, Istodax is a micro-earner for Bristol Myers so pulling one of its two indications won’t make much of a difference in terms of the drugmaker’s topline. But the results are notable as part of an industrywide reckoning for cancer drugs that earn the FDA’s accelerated nod and eventually flop confirmatory studies.


Just last week, Bristol Myers pulled its US indication for checkpoint inhibitor Opdivo as a monotherapy for hepatocellular carcinoma in patients previously treated with sorafenib after an FDA Oncologic Drugs Advisory Committee recommended pulling the nod.


Opdivo won an accelerated approval as a second-line treatment for HCC back in 2017, becoming the first immunotherapy to get OK’d for this indication. But two years later, a confirmatory study didn’t meet statistical significance in its primary endpoint of overall survival. Last March, the drug landed another, separate accelerated approval in combination with Yervoy for the same setting.


Opdivo in monotherapy HCC was one of two indications ODAC voted against out of a six-indication review. The other indication receiving a no-vote was Merck’s Keytruda as a third-line treatment for stomach cancer, which Merck opted to withdraw earlier in July.

https://endpts.com/bristol-myers-pulls-lymphoma-indication-for-istodax-after-confirmatory-trial-falls-flat/

Sanofi offers to buy U.S. mRNA partner Translate Bio

 Sanofi has offered to buy U.S. biotech company Translate Bio, two sources familiar with the situation said on Monday, as the French drugmaker bets on next-generation mRNA technology after setbacks in the COVID-19 vaccine race.

An offer for all Translate Bio shares had been made to the U.S. group's shareholders, the sources said. The persons declined to be identified due to the confidentiality of the talks.

Translate's board was expected to meet later on Monday to discuss the offer, one of the sources said. The second source said Sanofi's directors had met on Sunday to discuss the potential deal.

A spokeswoman for Sanofi declined to comment and Translate Bio did not respond to requests by email and phone for comment.

Financial terms of the offer were not known. Translate Bio's market value has soared fivefold since the start of the pandemic, to about $2.2 billion as investors have piled in to the sector amid a rush to develop vaccines and treatments to tame the pandemic which has killed 4.3 million and roiled the global economy. Translate Bio's shares hit an all-time intraday high on Thursday of $36.98. If successful, the takeover would mark the latest interest by a large pharmaceutical company in mRNA technology, following its proven success in COVID-19 vaccines developed by Pfizer/BioNTech and Moderna. The messenger RNA (ribonucleic acid) approach, an area of Translate Bio expertise, instructs human cells to make specific proteins that produce an immune response to a given disease. Sanofi and Translate Bio have been working together since 2018 and joined forces last year to develop an mRNA-based COVID-19 vaccine. They expect interim results of their Phase I/II clinical trial in the third quarter.

The two companies are also looking at mRNA vaccines for several infectious diseases and in June started a Phase I trial evaluating a possible mRNA-based vaccine against seasonal influenza, building on Sanofi's expertise as one of the world's top flu vaccine makers. Sanofi's interest comes after a tough year for the French drugmaker after falling behind rivals with less experience in the COVID-19 vaccine race, a major blow to CEO Paul Hudson who joined the company almost two years ago. Sanofi warned last year its traditional, protein-based COVID-19 jab developed with GlaxoSmithKline showed an insufficient immune response in older people, delaying its launch until toward the end of 2021. Hudson has also been under increasing pressure to reduce the company's dependence on its star eczema treatment Dupixent to boost earnings. Earlier this year, it agreed to fill and pack millions of doses of shots made by Pfizer/BioNTech, Johnson & Johnson and Moderna. Translate Bio, set up in 2016, has not launched any drugs on the market but its clinical-stage pulmonary product using its mRNA platform is being tested as an inhaled treatment for cystic fibrosis in a Phase I/II clinical trial, its website says.

https://finance.yahoo.com/news/exclusive-sanofi-offers-buy-u-214055330.html

'A Few Mutations Away': The Threat of a Vaccine-Proof Variant

 The Centers for Disease Control and Prevention (CDC) Director Rochelle Walensky, MD, MPH, made a dire prediction during a media briefing this week that, if we weren't already living within the reality of the COVID-19 pandemic, would sound more like a pitch for a movie about a dystopian future.

"For the amount of virus circulating in this country right now largely among unvaccinated people, the largest concern that we in public health and science are worried about is that the virus…[becomes] a very transmissible virus that has the potential to evade our vaccines in terms of how it protects us from severe disease and death," Walensky told reporters on Tuesday. 

A new, more elusive variant could be "just a few mutations away," she said.

Dr Lewis Nelson

"That's a very prescient comment," Lewis Nelson, MD, professor and clinical chair of emergency medicine and chief of the Division of Medical Toxicology at Rutgers New Jersey Medical School in Newark, told Medscape Medical News.

"We've gone through a few mutations already that have been named, and each one of them gets a little more transmissible," he said. "That's normal, natural selection and what you would expect to happen as viruses mutate from one strain to another."

"What we've mostly seen this virus do is evolve to become more infectious," said Stuart Ray, MD, when also asked to comment. "That is the remarkable feature of Delta — that it is so infectious."

He said that the SARS-CoV-2 has evolved largely as expected, at least so far. "The potential for this virus to mutate has been something that has been a concern from early on."

Dr Stuart Ray

"The viral evolution is a bit like a ticking clock. The more we allow infections to occur, the more likely changes will occur. When we have lots of people infected, we give more chances to the virus to diversify and then adapt to selective pressures," said Ray, vice-chair of medicine for data integrity and analytics and professor in the Division of Infectious Diseases at Johns Hopkins School of Medicine in Baltimore, Maryland.


"The problem is if the virus changes in such a way that the spike protein — which the antibodies from the vaccine are directed against — are no longer effective at binding and destroying the virus, and the virus escapes immune surveillance," Nelson said.

If this occurs, he added, "we will have an ineffective vaccine, essentially. And we'll be back to where we were last March with a brand-new disease."

Technology to the Rescue?

The flexibility of mRNA vaccines is one potential solution. These vaccines could be more easily and quickly adapted to respond to a new, more vaccine-elusive variant.

"That's absolutely reassuring," Nelson said. For example, if a mutation changes the spike protein and vaccines no longer recognize it, a manufacturer could identify the new protein and incorporate that in a new mRNA vaccine.

"The problem is that some people are not taking the current vaccine," he added. "I'm not sure what is going to make them take the next vaccine."

Nothing Appears Certain

When asked how likely a new strain of SARS-CoV-2 could emerge that gets around vaccine protection, Nelson said, "I think [what] we've learned so far there is no way to predict anything" about this pandemic.

"The best way to prevent the virus from mutating is to prevent hosts, people, from getting sick with it," he said. "That's why it's so important people should get immunized and wear masks."

Both Nelson and Ray pointed out that it is in the best interest of the virus to evolve to be more transmissible and spread to more people. In contrast, a virus that causes people to get so sick that they isolate or die, thus halting transmission, works against viruses surviving evolutionarily.

Some viruses also mutate to become milder over time, but that has not been the case with SARS-CoV-2, Ray said.

Mutations Not the Only Concern

Viruses have another mechanism that produces new strains, and it works even more quickly than mutations. Recombination, as it's known, can occur when a person is infected with two different strains of the same virus. If the two versions enter the same cell, the viruses can swap genetic material and produce a third, altogether different strain.

Recombination has already been seen with influenza strains, where H and N genetic segments are swapped to yield H1N1, H1N2, and H3N2 versions of the flu, for example.

"In the early days of SARS-CoV-2 there was so little diversity that recombination did not matter," Ray said. However, there are now distinct lineages of the virus circulating globally. If two of these lineages swap segments "this would make a very new viral sequence in one step without having to mutate to gain those differences."

"The more diverse the strains that are circulating, the bigger a possibility this is," Ray said.

Protected, for Now

Walensky's sober warning came at the same time the CDC released new guidance calling for the wearing of masks indoors in schools and in any location in the country where COVID-19 cases surpass 50 people per 100,000, also known as substantial or high transmission areas.

On a positive note, Walensky said: "Right now, fortunately, we are not there. The vaccines operate really well in protecting us from severe disease and death."

https://www.medscape.com/viewarticle/955691

US Employers Ratchet Up the Pressure on the Unvaccinated

 Employers are losing patience with unvaccinated workers.

For months, most employers relied on information campaigns, bonuses and other incentives to encourage their workforces to get the COVID-19 shot. Now, a growing number are imposing rules to make it more onerous for employees to refuse, from outright mandates to requiring the unvaccinated to undergo regular testing.

Among employers getting tougher are the federal government, the state governments of California and New York, tech giants Google and Facebook, the Walt Disney Co. and the NFL. Some hospitals, universities, restaurants, bars and other entertainment venues have also started requiring vaccines.

But the new measures are unlikely to affect many of the millions of unvaccinated Americans.

Many of the companies that are requiring shots have mostly office workers who are already largely vaccinated and are reluctant to work alongside those who aren't.

An employee assembles a circuit-board element before a ceremony to mark the opening of a Nanotronics manufacturing center in Brooklyn, NY. Matthew Putman, CEO of Nanotronics, said he agonized over his decision to impose a vaccine mandate on his more than 100 employees.

In contrast, major companies that rely on low-income blue-collar workers — food manufacturers, warehouses, supermarkets and other store chains — are shying away from mandates for fear of driving away employees and worsening the labor shortages such businesses are facing.

Tyson Foods, for instance, said about half of its U.S. workforce — 56,000 employees — has received shots after the meat and poultry processor hosted more than 100 vaccination events since February. But the company said it has no plans to impose a mandate to reach the other half.

Walmart and Amazon, the country's two largest private employers, have also declined to require its hourly workers to get vaccinated, continuing to rely on strategies such as bonuses and onsite access to shots. But in a potentially powerful signal, Walmart said  employees at its headquarters will be required to get vaccinated by Oct. 4.

The biggest precedent so far has come from the federal government, the nation's largest employer. President Joe Biden announced last week that all federal employees and contractors must get vaccinated or put up with weekly testing and lose privileges such as official travel.

The federal government has said it will cover the costs of the weekly tests. As for other employers, insurance may pay for such testing at some workplaces but not others.

Biden's decision could embolden other employers by signaling they would be on solid legal ground to impose similar rules, said Brian Kropp, chief of research at consulting firm Gartner's human resources practice.

But Kropp said some companies face complicated considerations that go beyond legalities, including deep resistance to vaccines in many states where they operate.

Retailers like Walmart might have a hard time justifying vaccine requirements for their workers while allowing shoppers to remain unvaccinated, Kropp added. Stores have mostly avoided vaccine requirements for customers for fear of alienating them and because of the difficulty in trying to verify their status.

In surveys by Gartner, fewer than 10% of employers have said they intend to require all employees to be vaccinated.

But a shift is building amid frustration over plateauing vaccination rates and alarm over the spread of the more contagious delta variant.

On Monday, the U.S. finally reached Biden's goal of dispensing at least one shot to 70% of American adults — but a month late and amid a fierce surge that is driving hospital caseloads in some places to their highest levels since the outbreak began. The president had hoped to reach his target by the Fourth of July.

The Union Square Hospitality Group, a group of New York City restaurants and bars founded by Danny Meyer, is now requiring employees and customers to be vaccinated by Sept. 7.

The San Francisco Bar Owner Alliance, a group of about 300 bars, made a similar decision following a meeting where "the thing that stood out was anger and frustration" toward vaccine holdouts, said founder Ben Bleiman.

While some companies fear vaccine mandates will drive workers away, the pandemic itself is also causing absenteeism. Bleiman said he recently had to close his bar for a night after his bartender, who was fully vaccinated, tested positive and a replacement couldn't be found.

Some employers are concluding that requiring vaccines is simpler than trying to come up with different rules on masks and social distancing for the small number of unvaccinated employees.

BlackRock, the global investment manager, is allowing only vaccinated workers into its U.S. offices for now and said people will be free to go maskless, as local health guidelines allow, and sit next to each other and congregate without restrictions. The firm said 85% of its U.S. employees are vaccinated or in the process of getting shots.

Matthew Putman, CEO of New York-based high-tech manufacturing hub Nanotronics, said he agonized over his decision to impose a vaccine mandate on his more than 100 employees. As it turned out, nearly all of them were already vaccinated, though he dreads the prospect of having to fire any holdouts.

"I hate the thought. But if it has to happen it has to happen," Putman said. "I lost a ton of sleep over this but not as much sleep as I've lost over the fear of infection."

Other mandates could provide a clearer test of the potential for employee backlash.

Hospitals and nursing home chains, for instance, are increasingly requiring the vaccine. So far, such mandates have survived legal challenges. More than 150 employees at a Houston hospital system who refused to get the COVID-19 shot were fired or resigned after a judge dismissed an employee lawsuit over the requirement.

Atria Senior Living, which operates more than 200 senior living communities across the country, was among the first to mandate vaccines for its staff in January.

It worked. Nearly 99% of Atria's 10,000 employees are vaccinated, and only a tiny fraction quit over the requirement, said CEO and Chairman John Moore.

"Our residents deserve to live in a vaccinated environment. Our staff deserves to work in a vaccinated environment," Moore said.

https://www.medscape.com/viewarticle/955859

Aiming Antibodies at Coronaviruses, Adagio Targets $318 Million IPO

 Waltham, Mass.-based Adagio Therapeutics set the terms for its initial public offering, hoping to raise up to $318.6 million. It is offering 17.7 million shares with an expected price between $16 and $18 per share. It will trade on the Nasdaq under the ADGI ticker symbol.

The company’s focus is on developing antibody-based therapies for infectious diseases with pandemic potential. On July 26, it inked a partnership with Biocon Biologics. Under the deal, Adagio will provide Biocon with supplies and expertise to manufacture and commercialize an antibody treatment based on its lead product candidate, ADG20, in India and other specific emerging markets.

ADG20 is a potent, long-acting, broadly neutralizing antibody that can be used to both treat and prevent COVID-19. It can be used as a monotherapy or in combination with other treatments. In non-clinical studies, it has been shown to neutralize SARS-CoV-2, the virus that causes COVID-19, including variants of concern, in addition to a variety of other SARS-like viruses.

The antibody is currently being studied in two separate Phase II/III clinical trials. The STAMP trial is evaluating the antibody in non-hospitalized COVID-19 patients. The EVADE trial is looking at it for the prevention of COVID-19.

“This partnership underscores the commitment of two companies to come together in order to make a significant impact on global health,” said Tillman Gerngross, co-founder and chief executive officer of Adagio. “At Adagio, we spent a lot of time engineering a highly differentiated molecule in our global fight against COVID-19, and, from the beginning, our metric of success was focused on how many lives we can touch. We expect this partnership to rank very highly on the ‘lives touched’ scale, which was the driver behind pursuing this agreement. Importantly, Biocon’s extensive manufacturing capabilities will enable large-scale production, making this potentially life-saving drug broadly available to millions of people who otherwise would not have access to this type of therapy.”

Biocon will pick up the rights to manufacture and market the treatment in India and other select emerging markets based on a commercial process developed for the antibody. They will have access to data from Adagio’s two trials and access to the Emergency Use Authorization package it is preparing in addition to regulatory submissions in order to look for approval or emergency authorization in India and other markets. No financial details were disclosed.

In April, Adagio completed a $336 million Series C financing. The round was led by RA Capital Management. Participating new investors included Redmile Group, Federated Hermes, Foresite Capital, ArrowMark Partners, PremjiInvest, and another leading healthcare investor. Existing investors also participated, including Fidelity Management & Research Company, OrbiMed, Polaris Partners, Mithril, GV, Population Health Partners, Adimab and Omega Funds.

That money is being used to advance ADG20.

The company was founded in 2020 by Gerngross and Laura Walker. In November 2020, it completed a Series B round worth $80 million, and in July 2020, a Series A worth $50 million.

“The COVID-19 pandemic continues to be a major health crisis worldwide, and even with emergency use authorizations for vaccines and antibody-based therapies, there remains a significant need for medications to treat and prevent COVID-19 infection,” Gerngross said in an April statement. “We are advancing ADG20 through a rapid development strategy based on preclinical data that demonstrate its best-in-class potential for treating all known variants of COVID-19 today.”

https://www.biospace.com/article/adagio-ipo-to-raise-318-6-million/

Ipsen, Exicure to Collaborate on Rare Neurodegenerative Disorder Therapies

 

  • Ipsen obtains exclusive options to Spherical Nucleic Acids (SNAs™) currently under discovery evaluation for Huntington’s disease and Angelman syndrome

  • Exicure will be responsible for discovery and certain pre-clinical development activities. In the event Ipsen exercises its option to the two programs, Ipsen will be responsible for further development and worldwide commercialization

  • Exicure will receive a $20m upfront payment and is eligible to receive up to $1B in option exercise fees and milestone payments should Ipsen opt into both programs, as well as tiered royalties

Fed's Waller: 'Go early and go fast' on taper

Federal Reserve Governor Christopher Waller on Monday said the U.S. central bank could start to reduce its support for the economy by October if the next two monthly jobs reports each show employment rising by 800,000 to 1 million, as he expects.

There's "no reason" to go slow on tapering the Fed's bond purchase program, Waller said in an interview on CNBC.

"If the jobs reports come in as I think they're going to in the next two reports then in my view with tapering we should go early and go fast, in order to make sure we're in position to raise rates in 2022, if we have to," he said, adding that he could see an announcement in September and the first slowdown in purchases in October.

That's a few months earlier than most on Wall Street are expecting, and quicker than Fed Governor Lael Brainard suggested she'd be open to in remarks made on Friday .

An increase of some 1.6 million to 2 million jobs over the next two reports - the first of which is due out this Friday - would mean that the economy will have regained 85% of its job losses by the beginning of September, Waller said.

"There's no reason you'd want to go slow on the taper, to prolong it - you want to get it done and get it over."

https://www.reuters.com/business/feds-waller-could-start-taper-by-october-no-reason-go-slow-2021-08-02/