More on mRNA Vaccine Manufacturing

 By Derek Lowe 

Here’s a good article from the Washington Post that updates some details that I talked about in this post on the lipids used in the mRNA vaccines and in this one about their overall manufacturing process. It focuses on Acuitas, who make the two proprietary lipids that are used in the Pfizer/BioNTech vaccine. Actually, if you go back a step, you get to Avanti Polar Lipids down in Alabaster, AL (as mentioned in Jonas Neubert’s terrific dive into the supply chains for these vaccines). Update: fixed some hosed-up links.

As you would imagine, everyone involved is having quite a time meeting demand. As the article says, though, it’s hard to get a clear picture of where the exact pinch points are, because the terms of the various contracts are not public, nor are even the identities of the raw material suppliers further up the chain. But anyone who’s had to source intermediates or starting materials in the drug business at any kind of scale will appreciate that the fastest way to find out what those weak points are is to place a Big Ol’ Order for something.

Among the interesting things you can uncover with that experiment is that what looks like several suppliers for Important Ingredient X are nothing of the kind, because they’re all (surprise!) sourcing it from the exact same place, likely as not somewhere back in China. That effect definitely happens with the Chinese suppliers themselves – a list of supposed sources across southern China will turn out, on closer inspection, to resolve to a single shop out in Chengdu or (even more worryingly) a bunch of drums in a warehouse near Shanghai from a big manufacturing overrun a few years back. The general tendency of many suppliers in every country to give you quotes for things that they don’t quite have yet, but are pretty sure they can round up if you place an actual order, also has to be taken into account.

In this case, you can be sure that everyone got down to the proverbial brass tacks very quickly, but it seems clear that there have been some difficulties sourcing starting materials on the scale needed and/or running some of the chemistry. These lipids involve multistep syntheses, and that’s just going to chew up time no matter what. This article at C&E News will give you some more details on that process, and I especially like this part:

Matthieu Giraud, global director of CordenPharma’s peptides, lipids, and carbohydrates business, says the synthesis requires about 10 steps and several product isolations. A complete manufacturing campaign is measured in months.

That does sound delightful. That team gets eaten up by all kinds of things: what sorts of purification are needed before the next step can be run, what the batch-versus-continuous-processing landscape is like, what scale the chemistry can be done at in the first place, and how that matches up with the sheer physical capacity of the plants doing the work. That scaling question alone is the door to a world of headaches: maybe one of the steps has an exotherm in its chemistry, which can mean special mixing conditions and size limitations. Or the product is especially thick and viscous and is thus harder to transfer and purify. There might be something tricky about the addition of a particular reagent – it’s corrosive unless you use certain alloys, or has to be warmed up to flow reliably and not all your reactors have that capability, or it doesn’t mix easily when it goes into the bulk reaction, or maybe something is theoretically available from several suppliers, but only one of them can furnish it in the sort of pellets that work best on scale. It goes on and on.

The topic of mixing brings up the formulation question that is one of the key steps in the whole process, forming the lipid nanoparticles with the appropriate amount of mRNA in each. I found this part quite interesting:

Companies have had to build equipment from scratch, including machines that shoot two streams of solution — one containing mRNA and one containing lipids — into a high-speed collision to fuse the nanoparticles and encapsulate the genetic payload. 

Exactly the sort of thing I was picturing here. No, this is a pretty weird process compared to most production lines. There are two ways to look at this whole business, and they both have validity. The first is “Why the hell didn’t we anticipate this? Why didn’t we put more money into the raw materials supply chain and the manufacturing capacity, and plan for success?” I’m sure that there are parts of this that could have been done better, but at the same time I’m also sure that Acuitas and the other players in this area have been scrambling since early last year to try to meet a vastly scaled-up demand as well (that C&E News story above confirms this). Some of these problems could have been solved or at least ameliorated by throwing money at them, and some couldn’t – and remember, buckets of money were in fact showered on every part of the process. But even more could quite possibly have helped.

The second viewpoint is to be struck by how much we’ve been able to scale up these things anyway. That might sound too happy and rosy, but there’s something to this take as well. When you look at that WaPo article, one thing that hits you is that the Acuitas people and others who have been involved in this area for a long time are stunned by how far it’s come and how quickly. I’d be willing to bet that if you’d called any of them up in (say) December 2019 and asked them if they could get to where they actually are by February 2021 they’d have been terrified.

My guess is that the truth is in between those two: I certainly doubt that the mRNA scaleup process has been flawless, but I don’t think that people have exactly been bumbling around, either. I continue to be thrilled that the vaccines work, and work as well as they do, and I will be rolling up my sleeve for them the first chance I get.

https://blogs.sciencemag.org/pipeline/archives/2021/02/22/more-on-mrna-vaccine-manufacturing

Anthem-backed digital startup Sharecare goes public in $3.9B blank check deal

 

• Digital health company Sharecare is going public via a blank check merger, along with a healthy investment from major insurer Anthem, in a deal valuing the startup at $3.9 billion.
• As part of the transaction expected to close in the second quarter, Sharecare will merge with special purpose acquisition company Falcon Capital Acquisition Corp. to create a new, publicly traded company. The deal will raise about $400 million for Sharecare, which it plans to use to expand its sales team and new product lines and embark on future M&A, the company said.
• Anthem has pledged to invest at least $25 million in Sharecare in a concurrent private placement, according to a preliminary prospectus filed with the SEC last Tuesday.

As utilization of digital health tools becomes more mainstream during COVID-19, payers have been upping their tech investments to streamline back-end functions, create cohesive consumer platforms and better target care.

Indianapolis-based Anthem has definitively pledged to invest $25 million in Sharecare prior to the deal's close, but could increase its initial investment to $50 million if both parties decide before mid-March, according to the prospectus.

Anthem already held a 25% equity investment in doc.ai, a healthcare artificial intelligence startup that Sharecare signed an agreement to acquire late January for $175 million.

Atlanta-based Sharecare, founded by WebMD founder Jeff Arnold and medical TV personality Mehmet Oz in 2010, aims to help consumers manage different elements of their health in one platform.

Since launching its platform in 2012, the company has grown to 64,000 employer clients covering more than 7 million eligible lives and roughly 6,000 health system customers.

Sharecare brought in $330 million in revenue last year, and projects that'll increase to $396 million in 2021 and $629 million by 2023, according to an investor presentation on the deal.

Sharecare hopes the influx of cash brought by entering the public markets will give it an advantage in the increasingly competitive virtual care space. The digital health market saturation is a key risk for Sharecare, with management noting in its prospectus it's a rapidly evolving industry undergoing significant technological change and shifting regulations, and there's a limited window to capture market share.

Falcon, led by the brother of former U.S. Treasury Security Steve Mnuchin, signed a letter of intent and term sheet with Sharecare in November, but the deal's been in the works since October. On closing, Falcon will own about 20% of the new company, inclusive of the private investment in public equity (PIPE) investors, which include Koch Strategic Platforms and Baron Capital Group, among others.

The transaction is being funded through a combination of $345 million in cash from Falcon, along with $435 million from the PIPE at $10 per share, and the Anthem investment.

The deal value represents about 9.5 times Sharecare's estimated 2021 revenue.

More and more healthcare companies looking to go public during the COVID-19 health tech craze have hopped on the blank check bandwagon in recent months. SPAC mergers are rising in popularity among founders and investors looking for guaranteed access to capital, while retaining more control of their company.

Over the past few months, numerous tech-focused health startups have taken this route, including SOC Telemed, Hims & Hers, Clover Health, Butterfly Network, Talkspace and 23andMe.

Sharecare will be listed on the Nasdaq under the ticker "SHCR." Arnold will stay on as CEO.

https://www.healthcaredive.com/news/anthem-backed-digital-startup-sharecare-goes-public-in-39b-blank-check-de/595213/

COVID-19 costs, care deferrals came back to bite insurers in Q4 2020

 While health plans reported sky-high profits in the early parts of 2020 due to care deferred under the pandemic, rising costs related to COVID-19 and more stable care utilization dinged their finances in the fourth quarter.

Cigna was the most profitable of the major national insurers in the fourth quarter, bringing in $4.1 billion in earnings for the quarter. 

While those profit numbers fell short of the expectations of Zack's analysts, Cigna's profits far outpaced its competitors in the quarter. In second place was UnitedHealth Group, with $2.2 billion in profits.

CVS Health earned $973 million in profits for the fourth quarter, and Anthem brought in $551 million.

Humana and Centene Corporation, meanwhile, both reported losses in the fourth quarter, with Centene posting a $12 million loss and Humana reporting $274 million in losses.

Through much of 2020, payers warned that they would feel the impacts of the coronavirus pandemic in the latter half of the year. Across the board, the companies said they saw spikes in costs related to COVID-19, and those costs were not offset as care utilization ticked up in tandem.

Cigna's chief financial officer Brian Evanko said, for example, that in the second quarter care deferrals largely offset costs related to the pandemic. In the third quarter, COVID-19 costs were on par with savings from lower care use, he said.

By the fourth quarter, COVID-19-related costs had outpaced any savings from deferred care, Evanko said.

Humana executives told investors that the insurer saw notable increases in COVID-19 hospitalizations across almost all of its markets. While care use was down about 15% in the quarter, that was not enough to offset the spike in COVID-19 costs.

Humana warned executives back in the third quarter that a loss was likely looming as COVID-19 cases mounted.

Anthem, CVS, Centene and UnitedHealth all cited similar concerns in their fourth-quarter reports.

Despite the challenges in the quarter, though, these payers were all profitable for full-year 2020, according to the reports. UnitedHealth Group led the way in 2020 profits, bringing in $15.4 billion.

Cigna brought in $8.5 billion in profit for 2020, with CVS close behind at $7.2 billion. Anthem earned $4.6 billion in profit for the year, followed by Humana with $3.4 billion and Centene with $1.8 billion.

A common boost? Medicare Advantage. 2020 marked a significant year of growth for many payers in the space, and they're planning to continue that expansion in 2021.

Anthem, for example, said its Medicare Advantage membership was up 18% in 2020. UnitedHealthcare expects to add 900,000 new Medicare members this year across individual, group and dual special needs coverage, executives told investors.

Centene's acquisition of WellCare, which was finalized in early 2020, also grows its reach in Medicare Advantage significantly.

And while CVS' Aetna subsidiary is planning further Medicare Advantage expansion, much like its peers, executives said it's also eyeing a reentry into the Affordable Care Act exchange market beginning in 2022. Aetna fully exited the exchanges in 2018 amid mounting losses.

https://www.fiercehealthcare.com/payer/covid-19-costs-care-deferrals-came-back-to-bite-insurers-q4-2020

Murthy's Multimillion Dollar Conflicts Are Cause for Concern

 Over the weekend, Dan Diamond for the Washington Post reported that Vivek Murthy, MD, nominated for Surgeon General and to help the Biden COVID-19 response, received 2.6 million dollars in pandemic consulting fees and speaking engagements since January 2020. Murthy received $400,000 from Carnival cruise lines for consulting, over $400,000 in cash and another $400,000 worth of stock from Airbnb, nearly $300,000 from Estee Lauder, and $600,000 from Netflix. The article notes, "most of Murthy's consulting work came after Biden effectively cinched the Democratic nomination in April 2020, after rival Sen. Bernie Sanders dropped out of the race, and he was sometimes touted in speeches as a Biden adviser."

What's the problem?

These payments are a serious conflict of interest, and an example of the swamp that Americans want to drain. These companies aren't paying exorbitant fees for advice or services provided. Sars-Cov-2 is a great threat, but no one has two million dollars of special advice. Most experts know that distancing, ventilation, hand hygiene, cleaning, and masking are key. As for Carnival cruise lines, my advice would be simple: don't run cruises. That advice is free, by the way.

If these payments cannot be for services rendered, what are they for? They are payments for influence. All of these companies have pending issues right now with the Biden transition and administration. For example, Carnival wants to reopen their cruise ships, so they want Federal exemptions, and attainable ventilation standards; Airbnb wants to use Murthy's name and title to assure customers it's safe to stay; Netflix has a dual interest: they want customers to purchase their services, making lockdowns good for business, but they simultaneously must produce shows, so exemptions for filming would be great; the list goes on.

Murthy is actively shaping decisions that impact these company's profits. If someone gave me $400,000, I would hate to anger them. Payments of this magnitude inherently compromise Murthy's ability to think only about what is best for the public. These conflicts should disqualify him from the post of Surgeon General.

What is financial conflict of interest?

If a company profits from certain activities but not others, and you take money from that company, a conflict has been created. If Pfizer pays a doctor $200,000 in speaking fees, that doctor has a conflict any time they talk about or prescribe Pfizer drugs or any other drug that could be used in conjunction with or in lieu of Pfizer drugs. If Pfizer gives the money to a cancer patient advocacy organization who then gives it to the researcher, the conflict still exists, particularly if the source of funding is obvious to all involved.

Murthy received over $150,000 for a book. To me, this isn't a conflict. For example, someone could write an argument for or against saturated fats. That person doesn't have a conflict when they say it a second time because they were free to choose initially. In contrast, if pharmaceutical company Celgene pays you, then the direction of bias was always towards promotion of their drugs.

Personal payments -- those that Netflix and Carnival gave directly to Murthy -- are more problematic than research payments, where a company gives money to a university to run a study.

Finally, small donors do not concern me. If a politician raises money five dollars at a time, as some do, that's not a conflict. Getting $5,000,000 from Chevron is. Philanthropic and non-profit research funding is a conflict if the funder has skin in the game -- for example, their finances are tied to a research conclusion. However, if they are not in that market, no conflict exists.

I am concerned when there is a revolving door between government and industry. Previously, Jeff Bien, now a Stanford fellow, and I studied the relationship between U.S. FDA reviewers and pharma. We found the single most common job for someone who left the FDA was pharma. Can someone regulate forcefully if they know they may someday work on the other side of the table?

The silence is deafening

Conflict of interest is problematic whether the person is on your "team" or not. Yet, many have been silent about Murthy. Elizabeth Warren famously criticized then FDA commissioner nominee Dr. Scott Gottlieb for financial conflicts -- and I was sympathetic to that criticism -- but here, "Warren's office did not respond to repeated requests for comment about Murthy's financial disclosures."

In May of 2020, Buzzfeed broke the story that the former CEO of JetBlue donated $5,000 to help fund the Santa Clara seroprevalence study. This money was not paid to the researchers personally, but a pooled research fund. Many academics on Twitter were harshly critical of the conflict. In Murthy's case, the sum of money is 400 times larger, and was paid to the nominee directly. Yet, Twitter has been quiet.

Of course, Twitter leans towards democrats and Dr. Gottlieb and JetBlue are perceived as being from the other team, while Murthy is perceived as being on our side. Standards of conflict of interest should not be selectively applied based on political affiliation. Every person critical of Gottlieb who is not critical of Murthy is engaged in hypocrisy.

Conflict is a serious issue

I have a disclosure. I am the author of at least 14 peer reviewed papers exploring financial conflict of interest, and I think a lot about it. For example, I have lectured at major pharmaceutical companies and declined all payment, room and board, and travel. I even packed my own thermos of coffee and ate nothing. I did this because I believe -- and the evidence shows -- that these conflicts affect the writing, thinking, and practice of medicine. I also wanted to show junior folks that it is possible to avoid personal ties to biopharmaceutical companies, and interact productively with them.

Yet, the message of the surgeon general nominee is the opposite. The nomination says it's absolutely fine to accept lavish sums of money for "advice," and then accept a position that allows for decisions that might be interpreted as "paying them back." Young people have lost a role model.

What if he didn't know he was going back into public service?

Some ask if these payments are problematic if Murthy did not think he would return to government service. Or alternatively, shouldn't Murthy be paid for advice?

Again, it's disingenuous to pretend the size of these payments is for advice. Even without a future position, these companies likely believe Murthy has significant influence in the democratic machine. He may know the Biden administration's plans for occupational standards, and shape them. If he thinks favorably about these companies, he may influence policy to their benefit.

Pandemic profiteers

There is a broader ethical issue: profiteering from a pandemic is offensive. Americans have lost jobs in record number and many are scrambling just to get enough food. At the same time, some are enriching themselves by consulting for teachers' unions, state and local governments, and businesses. If you are making money from suggesting restrictions, you might not be in the best position to tell society when restrictions should end. This problem extends beyond Murthy.

Government is a swamp

There is an old saying that politicians go to Washington to do good but stay to do well. This reflects the growing American sentiment that government is a swamp. The folks who work to promote the public interest quickly join the companies they used to regulate. They regulate favorably while in office, and afterwards, help companies find the loopholes. Americans are frustrated by this phenomenon. Although the last administration claimed to want to drain the swamp, it enlarged it instead. The Surgeon General nominee's conflicts of interest make that swamp larger.

We must call out conflict of interest regardless of political party or whether or not we like Murthy. There are tens of thousands of public health experts who have received zero dollars for giving COVID-19 advice -- we must pick our advisors from this set. We need a political party willing to cut the ties of corporate interests from the work of public servants. The Surgeon General used to be "America's doctor," but now he appears to look more like Netflix's and Carnival's doctor. Faith in public institutions is at stake at Thursday's confirmation vote.

Vinay Prasad, MD, MPH, is a hematologist-oncologist and associate professor of medicine at the University of California San Francisco, and author of Malignant: How Bad Policy and Bad Evidence Harm People With Cancer.

https://www.medpagetoday.com/blogs/vinay-prasad/91307

White House 'working to fix' federal COVID vaccine tracking system

 The U.S. government is working to correct problems with the federal system for tracking the shipment and administration of COVID-19 vaccines after state officials said it was not accurately reflecting the progress of the vaccine rollout, a top U.S. healthcare official said on Monday.

“We are actively working on the vaccine tracker, we recognize their challenges... and we are working to fix them imminently,” said Rochelle Walensky, director of the U.S. Centers for Disease Control and Prevention, said during a news briefing.

The CDC’s vaccine tracker said as of Monday morning that more than 75 million doses have been delivered to states and territories and around 64 million shots have been given.

https://www.reuters.com/article/us-health-coronavirus-white-house/white-house-working-to-fix-federal-covid-vaccine-tracking-system-says-official-idUSKBN2AM2IS

Pfizer: To ship 13 million COVID-19 vaccine doses per week to U.S. by mid-March

 Pfizer Inc expects to deliver more than 13 million doses of its COVID-19 vaccine per week to the United States by the middle of March, more than doubling its shipments from early February, a top Pfizer executive said in prepared testimony ahead of a Tuesday congressional hearing.

Pfizer has shipped around 40 million doses to locations across the United States so far and is on track to deliver 120 million doses of its two-dose regimen by the end of March, said John Young, Pfizer’s chief business officer.

He added that Pfizer is also prepared to provide a total of 300 million shots to the United States by the end of July and has raised global production expectations for 2021 to at least 2 billion doses.

In his own prepared remarks, Moderna Inc President Stephen Hoge said the drugmaker plans to deliver 100 million doses of its two-dose shot by the end of March, and 300 million by the end of July.

Johnson & Johnson believes it will be able to ship at least 20 million doses of its single-dose shot to the United States by the end of March after receiving U.S. regulatory authorization, said Vice President of Medical Affairs Richard Nettles. It expects to ship 100 million doses by mid-year 2021, it said.

The drugmakers’ remarks put the United States on track to receive 240 million doses by the end of March, enough to inoculate 130 million Americans, and 700 million doses by mid-year, more than enough to dose the entire U.S. population.

The comments were prepared ahead of a U.S. congressional hearing on vaccine availability to be held by the House Committee on Energy and Commerce on Tuesday.

https://www.reuters.com/article/us-health-coronavirus-usa-vaccines/pfizer-to-ship-13-million-covid-19-vaccine-doses-per-week-to-u-s-by-mid-march-says-executive-idUSKBN2AM2LW

Covid-19 Relief Bill Moves Closer to House Vote

 The House Budget Committee approved the $1.9 trillion coronavirus relief package Monday, setting up a vote in the full House later this week.

The Budget Committee on Monday officially fused together different portions of the legislation that had advanced earlier this month in nine different House committees. A full House vote is expected Friday or Saturday.

The bill moving through the House would extend $400-a-week unemployment benefits through Aug. 29, send $1,400 per-person payments to most households, provide billions in funding for schools and vaccine distribution, expand the child tax credit, broaden child-care assistance and bolster tax credits for health insurance. It would also increase the federal minimum wage to $15 an hour over four years, a point of division among Democrats.

"We are in a race against time. Aggressive, bold action is needed before our nation is more deeply and permanently scarred by the human and economic costs of inaction," House Budget Committee Chairman John Yarmuth (D., Ky.) said Monday before the vote. "We are going to pass this legislation and we are going to turn this pandemic and economic crisis around."

In the past month, new Covid-19 cases have declined as vaccines rolled out to more Americans, and economists have upgraded their outlooks for the year. But officials including Treasury Secretary Janet Yellen have said the $1.9 trillion package is needed to dig out of the economic slump induced by the pandemic.

Republicans have criticized the bill as wasteful and said Congress should take more time to assess where more funding is needed after lawmakers passed nearly $4 trillion in relief efforts since the pandemic began.

"This is the wrong plan at the wrong time and for all the wrong reasons, " Rep. Jason Smith of Missouri, the top Republican on the House Budget Committee said during the hearing. "The real reason for this bill is to send billions to bail out blue-state governors and reward their harmful lockdown policies," he said, referring to the bill's $350 billion in funding for state and local governments.

The committee voted largely along party lines to approve the bill Monday. Rep. Lloyd Doggett (D., Texas) mistakenly voted against the bill when he joined the hearing remotely as he was getting off a flight from Texas and misunderstood the vote, his spokeswoman said. "He supports the Covid-19 relief legislation," she said. It wasn't yet clear Monday afternoon if he could change his vote.

The bill is expected to narrowly pass in the House, where Democrats hold a 221-211 majority. It will then head to the Senate, where Majority Leader Chuck Schumer (D., N.Y.) said he was confident it would pass before enhanced unemployment benefits start to run out in mid-March.

"Democrats remain hard at work preparing the desperately needed Covid relief bill, which is on track to go to the president's desk before the March 14 expiration of unemployment insurance benefits," Mr. Schumer said on the Senate floor Monday.

But the bill has already started a messy fight in the Senate, where Democrats are divided over whether to include a provision that would gradually raise the minimum wage to $15 an hour over four years.

Two centrist Democrats, Joe Manchin of West Virginia and Kyrsten Sinema of Arizona, have already said they oppose including it in the relief bill. A larger group of 10 other Democrats haven't signed on to stand-alone legislation raising the minimum wage to $15 an hour.

Any dissension among Democrats is problematic in the evenly-divided Senate since Democrats can't afford to lose a single vote among their own ranks and still pass the legislation. They are preparing to use a process tied to the budget, known as reconciliation, that will allow them to pass certain bills with a simple majority, rather than the 60 votes most bills need. That will enable Democrats to pass the legislation without GOP votes in the 50-50 Senate, with Vice President Harris casting the tiebreaking vote.

But Senate rules require that measures passed under reconciliation must be directly tied to the budget, and it isn't clear that raising the minimum wage will be considered permissible. The nonpartisan parliamentarian of the Senate determines which measures are eligible to pass under reconciliation in a decision that could come as soon as Wednesday.

If the minimum wage increase is permitted to remain in the bill, Democrats might seek to craft a compromise that would raise the wage to a lower level, or phase it in over a longer period. Mr. Manchin has talked about supporting an increase to $11 or $12 an hour, according to activists who met with him last week.

President Biden has said he doesn't believe the Senate's rules will permit the minimum wage increase to remain in the bill, even though he supports raising it.

"The president would not have included an increase in the minimum wage if he did not want to see it in the final package," White House press secretary Jen Psaki told reporters Monday, but said the decision was up to the parliamentarian. "We'll see what comes out on the other end."

https://www.marketscreener.com/news/latest/Covid-19-Relief-Bill-Moves-Closer-to-House-Vote--32510062/