Valneva SE and Pfizer Inc. reported further positive Phase 2 data for their Lyme disease vaccine candidate, VLA15. Based on these new results, Valneva and Pfizer plan to proceed with a three-dose primary series vaccination schedule in a planned Phase 3 clinical trial. The trial will evaluate VLA15 in adults and pediatric subjects 5 years of age and above and is expected to be initiated in 2022, subject to regulatory approval. The Phase 2 trial, VLA15-221, compared the immunogenicity of VLA15 after administration of two (at months 0 and 6) or three (at months 0, 2 and 6) primary series doses in groups aged 5-11, 12-17 and 18-65 years. In the sub-analysis of adult participants (18-65 years old) who received VLA15 in either the two-dose schedule (N=90) or the three-dose schedule (N=97), performed one month after the last vaccination dose, VLA15 was found to be immunogenic with both vaccination schedules tested. These data are consistent with the strong immunogenicity profile observed for this age group in previous Phase 2 studies. However, the induction of anti-OspA IgG (anti-outer surface protein A immunoglobulin G) antibody titers was higher in participants who received the three-dose primary series compared to those who received the two-dose primary series, supporting the use of a three-dose primary series schedule in the planned Phase 3 clinical trial. The VLA15-221 trial is ongoing to assess the safety and immunogenicity of VLA15 in 5-17 year olds. Initial pediatric data are expected in the first half of 2022. The analysis was also consistent with the acceptable safety and tolerability profile observed in previous studies of VLA15. No vaccine-related serious adverse events (SAEs) were observed.
Friday, February 4, 2022
Bristol Myers posts slightly better-than-expected 4th-qtr results
Drugmaker Bristol Myers Squibb Co on Friday posted slightly better than expected fourth-quarter earnings on strong sales of blood thinner Eliquis and cancer drug Opdivo.
The company said it earned $4.07 billion in the quarter, or $1.83 a share, up from $3.33 billion or $1.46 a share, a year earlier. Analysts on average expected the compay to earn around $1.80 a share, according to Refinitv IBES data.
Revenue in the quarter was $11.99 billion compared with $11.07 billion in 2020. Sales of Eliquis rose 18% to $2.7 billion and sales of cancer immuniterapy rose 11% to $1.99 billion in the quarter.
Sales of the company's top-selling cancer drug Revlimid rose 1% to $3.33 billion in the quarter. That drug will have generic competition in the United States and internationally this year, and sales are expected to decline.
Bristol Myers still expects earnings and sales growth this year. The company forecast 2022 earnings per share of $7.65 to $7.95 a share. Analysts, on average, had forecast $7.86 a share for the year.
It also reiterated its 2022 sales forecast of $47 billion.
Regeneron quarterly profit nearly doubles on robust sales of COVID-19 therapy
Regeneron Pharmaceuticals (REGN.O) quarterly profit nearly doubled on Friday on strong sales of its COVID-19 antibody cocktail.
The company recorded $2.30 billion in sales of its COVID-19 antibody therapy, REGEN-COV, which helped its quarterly revenue soar 104% to $4.95 billion. Excluding revenue from REGEN-COV, the sales growth was 17%.
The U.S. Food and Drug Administration in January had revised its emergency use authorizations for COVID-19 antibody treatments from Regeneron and Eli Lilly (LLY.N) to limit their use, as the drugs were found to be unlikely to work against the Omicron variant.
"Given the lack of efficacy of REGEN-COV against the Omicron variant, we are working hard to develop next generation antibodies that are active against Omicron and all other variants of concern," said Leonard Schleifer, president and chief executive officer of Regeneron.
The drugmaker's net profit rose to $2.23 billion, or $19.69 per share, in the fourth quarter ended Dec. 31, from $1.15 billion, or $10.24 per share, a year earlier.
Arcellx Announces Pricing of IPO
Arcellx, Inc. (NASDAQ: ACLX), a biotechnology company reimagining cell therapy through the development of innovative immunotherapies for patients with cancer and other incurable diseases, today announced the pricing of its initial public offering of 8,250,000 shares of common stock at a public offering price of $15.00 per share. The gross proceeds from the offering, before deducting underwriting discounts and commissions and other offering expenses payable by Arcellx, are expected to be approximately $123.8 million. In addition, Arcellx has granted the underwriters a 30-day option to purchase up to an additional 1,237,500 shares of common stock at the initial public offering price, less underwriting discounts and commissions. All of the shares of common stock are being offered by Arcellx. Arcellx’s common stock is expected to begin trading on the Nasdaq Global Select Market on February 4, 2022, under the ticker symbol “ACLX.” The offering is expected to close on February 8, 2022, subject to the satisfaction of customary closing conditions.
BofA Securities, SVB Leerink, Barclays and William Blair are acting as joint book-running managers for the offering.
https://www.yahoo.com/now/arcellx-announces-pricing-initial-public-065700109.html
Thursday, February 3, 2022
Omicron, Its Mutations, and the Antibody Response
BY DEREK LOWE
Let's do a coronavirus post today, since there are some really good data out on the structure and function of the by-now-universal Omicron variant. As we have all been hearing, this one has a great number of mutations in the Spike protein region - via Eric Topol on Twitter, here's a visualization from Nextstrain of where Omicron sits in phylogenetic space compared to previous variants, annotated by Emma Hodcroft at Bern. You can see that it's an odd one, as advertised, pretty much off by itself and with its most recent common ancestor apparently coming from back in 2020 somewhere.
Nature has a good new article on the various theories for how this happened. That long arm poking out into Omicron territory on that phylogenetic tree tells you that we really didn't pick up on any of the (many) intermediate mutations along the way. It's possible that we just missed them in the wild as they spread from person to person, but a lot of people don't quite believe that. So it could have developed inside an immunocompromised patient whose body kept fighting it to a roughly even draw for months, allowing the virus to be under selection pressure the whole time without killing it off. Or it could have been a jump (back in 2020) into another species, with evolution there until it made the jump back into humans. My own guess is the immunocompromised patient, or maybe more than one. I think that the other explanation with multiple interspecies jumps is kind of a stretch, but we really don't have enough information yet to say anything with lots of confidence. It would be very good to know the answer, though, because we might then start some different forms of surveillance to keep from being taken by surprise again.
So what do all these mutations do for the virus? The first two links above gives us a few of those answers. The first paper has some very nice cryo-EM structural data of the Omicron virus and its binding to the human ACE2 protein, the second has similar data obtained via X-ray crystallography. This lets us see what at least a few of those mutated residues are doing. At right is an illustration from the cryo-EM paper showing the mutations in the Spike protein itself, shown as red balls. You can see a bunch of them in the actual receptor-binding domain (RBD), and some of these (like N501Y, T478K, and K417N) we've seen in other lineages.
For those outside the protein world, that notation is how we usually write mutated residues. Each protein has a numbering system, starting from the end that has a free amino group on it (the N-terminal) and going to the end that has a free carboxylic acid on it, the C-terminal. Every amino acid in the protein is numbered in sequence, so you can see that those three residues just mentioned are four or five hundred amino acids down from the N-terminal. And the single letters are the amino acid code that's used by molecular biologists and protein scientists around the world, as seen in this table. So when you say "K417N", that means that the lysine (K) that's normally at position 417 of the protein has been mutated to an asparagine (N). This information will make you a hit at parties, trust me, no matter how unappealing you may be otherwise.
The overall binding of Omicron's spike is about the same as Delta, so that's not what makes it special. In fact, a number of the mutations it has actually decrease its binding affinity, but those are made up for by others. The Q493R, G496S and Q498R residues seem to be doing that job, with those new arginines and the serine forming new salt bridges and hydrogen bonds. Meanwhile, that K417N mentioned above loses a nice salt-bridge interaction that was present in Delta.
So what are these mutations doing, if they're not making the Spike bind its target better? You guessed it: evading the usual antibodies to a greater degree. That's an argument for the chronic-infection-in-some-immunocompromised-patient theory, because this is what you'd expect to see after a long slugfest with human antibodies that could bind the surface of the virus but weren't quite enough to finish the infection off. The authors of both papers linked above conclude that the virus has been walking an evolutionary tightrope between antibody evasion and retaining binding to ACE2, and unfortunately hit on a combination that allowed it to do both, and this fits in with earlier work on the Omicron genome as well. The X-ray paper also picked up on a new surface modification on N370, a glycan reside attached to that asparagine, which can also help with the immune evasion as it sits in the binding footprint common to many antibodies.
This helps to explain the number of "breakthrough" infections of Omicron in previously-vaccinated people, but as soon as you say that you have to follow up with the fact that the vaccines also have done a remarkable job of keeping people out of the hospital, not to mention the ICU or the morgue. In country after country where these data have been collected, the previously unvaccinated have had remarkably greater chances of ending up with a serious infection from Omicron. We have been fortunate that the immune response brought on by vaccination has performed that well against a variant like this one that has a really long list of mutations compared to the original vaccination version of the Spike. Remember, when you say "immune evasion" you're not saying "total immune evasion" - I think many people have been confused by that point. Vaccination (and prior infection) raise a whole host of different antibodies, some of which are rendered less effective by Omicron's mutation profile and some of which aren't. People who have had the actual coronavirus can get up to even higher and more effective immunity by getting vaccinated on top of that.
And this also explains the way that Omicron has wiped out the effectiveness of some of the existing monoclonal antibodies (such as those from Lilly and Regeneron). This has recently become a political issue, with Florida's governor Ron DeSantis angrily protesting the FDA's statements about these antibodies becoming useless for treating Omicron patients. Various blowhards amplified this to the point of accusing the government of a conspiracy against Florida residents and others who were being treated with these antibodies, since many of these patients had also chosen to remain unvaccinated. The technical term that sums up this point of view is "horseshit". As opposed to the variety of antibodies that you would have from vaccination or prior infection, mAb therapy gives you only one or two, administered in large quantities from an outside i.v. And if the Omicron mutations keep those exact antibodies from binding to the virus, then you are just completely out of luck. That's what has happened - it's not a case of "Well, they should keep these on the market because they might still help someone". No, Omicron is now over 99% of all the coronavirus infections in the US, and these exact monoclonal antibodies are useless against Omicron. That ship has sailed.
Want a wider suite of antibodies than you can get from being dosed with a single monoclonal? Get vaccinated. If you've been infected, of course, you have a nice wide variety as well, but you got that while risking all the possible problems with the disease, ranging from sudden turns toward serious infection all the way to "Long Covid". None of which you will get from the vaccine. The risk/benefit for most adults seems extremely clear, which is why watching thousands of people die every day in a way that the huge majority of them could have prevented is so damned frustrating.
https://www.science.org/content/blog-post/omicron-its-mutations-and-antibody-response
Price of COVID treatments from Pfizer, Merck, GSK align with patient benefits -report
The prices of drugs used to treat COVID-19 for those at risk of serious illness are "reasonably aligned" with how much they help patients, according to a draft report from drug-pricing research organization the Institute for Clinical and Economic Review (ICER).
The report assessed Pfizer Inc's (PFE.N) Paxlovid and Merck & Co's (MRK.N) molnupiravir - both recently authorized antiviral pills - as well as sotrovimab, an intravenous monoclonal antibody drug developed by GlaxoSmithKline Plc (GSK.L) and Vir Biotechnology Inc (VIR.O).
The three treatments - approved on an emergency basis for people with mild-to-moderate COVID-19 deemed at risk of progressing to serious illness - have been purchased by the U.S. government and are being distributed free-of-charge to healthcare providers.
The U.S. government has paid around $530 for a 5-day course of Paxlovid, $700 per five-day course of molnupiravir, and $2,100 for a course of sotrovimab - the lone available antibody treatment shown to work against the now dominant Omicron variant of the virus.
In clinical trials, ICER said molnupiravir cut hospitalization rates for high-risk patients by 30%, compared with 88% risk reduction for Paxlovid and 79% for sotrovimab.
"Right now the alignment of the price and benefits look reasonable," ICER President Steve Pearson told Reuters.
The Pfizer and Merck drugs are meant to be taken at home, while GSK's antibody is administered in hospital or infusion centers.
ICER also analyzed the cost-effectiveness of fluvoxamine, a 40-year-old generic pill used to treat conditions such as obsessive-compulsive disorder and depression at a cost of about $10 for a 10-day course.
Researchers from the University of Minnesota applied in December for emergency authorization of fluvoxamine for high-risk COVID patients after studies showed that the anti-depressant, which also has anti-inflammatory properties, reduced hospitalization rates by 32%.
ICER uses a decades-old formula called the quality-adjusted life year (QALY) – the cost of one year of good health for one patient – to estimate fair value.
By that and other measures, ICER said fluvoxamine offers the best value at $6,000 per QALY gained. It calculated Paxlovid was second at $18,000 per QALY gained, followed by molnupiravir at $55,000 and sotrovimab at $69,000.
Pearson said the pandemic has lots of "moving parts" and if the risk of hospitalization from infection with Omicron or a future variant proves to be lower, ICER's analysis would change.
The analysis applies only to use of the drugs for patients at elevated risk of severe COVID-19. If the treatments were used in lower-risk populations, "their cost effectiveness would be significantly reduced," ICER said.
ICER plans to accept public comment on its draft and issue an updated evidence report in late March.
Canada Rules Out Use of Troops Against Truckers' Blockade; More Protests Planned
The Canadian government will not use troops against truckers whose nearly week-long protest of coronavirus vaccine mandates has brought traffic in central Ottawa to a halt, Prime Minister Justin Trudeau said on Thursday.
More than 200 trucks and other vehicles have been blockading downtown roads in the nation's capital since last Friday in what is an unprecedented protest by Canadian standards.
Organizers say drivers plan to hold similar protests in Toronto, the country's most populous city and its financial hub, and Quebec City later this week amid growing frustration over almost two years of restrictions imposed to fight COVID-19.
Ottawa residents are angry that local police are largely watching the demonstrations rather than moving in to break them up. The city's police chief on Wednesday indicated guns were being smuggled into the protest and said using the military was an option, but Trudeau dismissed the idea.
"There is no question of sending in the army," the prime minister said.
Some demonstrators want an end to a federal COVID-19 vaccine mandate for cross-border truckers while others insist Trudeau be removed from power on the grounds he exceeded his authority.
Protest organizer Tamara Lich said the demonstrators would stay in place until all mandates had been dropped.
"Our movement has grown in Canada and across the world because common people are tired of the mandates and restrictions in their lives that now seem to be doing more harm than good," she told a news conference.
A few people on Ottawa streets have brandished Nazi flags, harassed minorities and threatened reporters.
"That is unacceptable. It's time for these people to go home," Trudeau told reporters.
Ottawa police, who have made just three arrests so far, issued 30 traffic tickets on Wednesday.
The protesters have raised more than C$10 million ($7.9 million) on the crowdfunding platform GoFundMe, which has suspended disbursements while it checks on how the money is being spent.
Legislators on the House of Commons public safety committee voted on Thursday to summon GoFundMe representatives to testify about what safeguards it has in place when it comes to releasing the funds.
'LESSONS TO BE LEARNED'
Quebec Premier Francois Legault said authorities would not tolerate any mayhem related to protests. Quebec City Mayor Bruno Marchand told a radio station that "there are lessons to be learned from Ottawa."
Trudeau's Liberals look set to benefit politically from the protests, which have split the official opposition Conservative Party. Federal Conservative lawmakers ousted leader Erin O'Toole on Wednesday, citing his poor performance in an election defeat to the Liberals last September and his initial, lukewarm support for the protests.
Former Conservative leader Andrew Scheer and other parliamentarians later posed with truckers, a move Ottawa Mayor Jim Watson branded "an absolute disgrace."