Monoclonal antibodies should become the best selling drug in the world

While mRNA vaccines are currently the best selling drug in the world, they are not that safe and can lead to death and disability.  Monoclonal antibodies are actually the #1 intervention for COVID because they are both safe and effective.  Unfortunately for monoclonals, their broader adoption is held back by 2 false narratives:

1. COVID vaccines are safe.
2. Monoclonal antibodies duplicate what vaccines do.

Should the political winds change and my heretical viewpoints become mainstream, monoclonal antibodies could generate $200B+ every year.  Regeneron Pharmaceuticals, which has rights to the #1 monoclonal antibody treatment, has a market cap of only $69B.

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Vaccines and monoclonal antibodies don’t do the same thing

Firstly, vaccines have safety issues that monoclonal antibodies do not.  It is likely that the S1 portion of the spike protein causes vaccine injury (and long COVID).  Monoclonal antibody treatments do not have S1 spike protein and do not cause injuries resembling vaccine injury.  My previous post has some discussion regarding vaccine safety.  This is huge for monoclonal antibodies because their risk/benefit is far superior to vaccines.

Secondly, the protection provided by vaccines and monoclonals is not redundant.  Their protective effect seem to stack on top of one another.  What we know for sure is that fully vaccinated people do get infected.  Despite vaccination, they still see significant benefit from monoclonal antibodies.  An observational study found that monoclonal antibodies  reduced the hospitalization rate from 15.1% to 1.8% among fully vaccinated outpatients.

Here are some potential explanations:

1. The quality of antibodies from vaccination varies widely.  It takes time for the immune system to make higher quality antibodies through its trial and error process; there is a controlled mutation process where the immune system will try out new antibodies so that it can eventually stumble across more potent antibodies.  The trial and error process can stop before the body discovers high quality antibodies.  Monoclonal antibody treatments are designed by screening antibodies produced by humans/animals and selecting ‘superantibodies’ that are extremely potent.  This ensures that antibody potency is extremely high.
2. People who are the most likely to die from COVID tend to see much lower benefit from vaccination than everybody else.  There is something about their immune systems that makes vaccination less effective.  For example, many immunocompromised patients do not make detectable antibodies after being vaccinated.
3. New variants can break through the protection from vaccines.  Mutations can change the shape of the spike protein in a way that allows it to escape attack by existing antibodies.  This has already happened with the South African variant (B.1.135 / Beta), which significantly reduced the effectiveness of the Novavax and AstraZeneca vaccines.  While variants have broken through the protection from monoclonal antibodies, monoclonal antibody treatments can potentially be more robust against variants than vaccines.  Scientists can put together antibody cocktails which attack from several different angles, making it less likely that every part of the antibody cocktail will be broken.  Another way to think of it is that monoclonal antibodies have the potential to mount a much broader attack than vaccination can.

Humanity should NOT rely on vaccines for reliable protection against the coronavirus.  Vaccines aren’t reliable in people who need them the most and they can potentially fail even more if a new variant comes along.  I would think of vaccines and monoclonals as different layers of protection, with the monoclonal antibody layer having far less safety issues than vaccination.

Politics affect the adoption of monoclonal antibodies

There is an ongoing political battle over whether or not the FDA should be weaponized as part of the culture wars.

1. The Biden administration wants the FDA to participate in a war against the unvaccinated.  The culture war strategy more or less boils down to “might makes right”.  Objective truth does not matter if you destroy your enemies and scare everybody into going along with your political agenda.
2. Some top FDA officials just want to make money and don’t want to unnecessarily risk the FDA’s credibility.  Those officials are likely aware that 2 people (Brianne Dressen, Maddie de Garay) became disabled during the COVID vaccine clinical trials.  The officials are aware that their agency would lose credibility if the FDA were to go too far and approve every unsafe drug being developed.

So far, the Biden administration has been winning that war.  FDA officials Marion Gruber and Philip Krause resigned over their disagreement with the Biden administration’s booster plan (you can read the ex-commissioners’ opinion piece that was published in The Lancet).

The ‘war on the unvaccinated’ is a problem for monoclonal antibody adoption because it favours politicized views about vaccines.  Those promoting the ‘pandemic of the unvaccinated’ rhetoric won’t go along with the idea that monoclonal antibodies are heavily underutilized; doing so would imply that vaccines aren’t safe and don’t make people invulnerable against COVID.

I don’t know when the political winds will change, if they will even change at all.  However, I would point out that the political winds shifted very rapidly between 2020 and 2021.  Last year, CNN and Kamala Harris promoted the idea that the rushed COVID vaccines are unsafe because they wanted to discredit Donald Trump and his role in Operation Warp Speed.  Fast forward to 2021 and these same people are pushing for a segregated society based on vaccination status.  There’s a good chance that these people will move onto the next political battleground because vaccine apartheid will lose votes from unvaccinated voters.

How monoclonal antibodies can and should be used

On lab animals, it has been shown that monoclonal antibodies are more effective the earlier they are administered.  They work by slowing/stopping viral reproduction and don’t do anything if the host has already killed off all of the virus.  While viral debris from dead virus is likely responsible for the death of patients, monoclonals only work when they are applied early enough to reduce the build-up of such viral debris.

The ineffectiveness of monoclonal antibodies has been demonstrated in humans.  In the RECOVERY study, Regeneron’s monoclonal antibodies had no meaningful effect because waiting for a patient to become hospitalized was too late.  The REGEN-COV arm (Casirivimab Plus Imdevimab) had a mortality rate of 20% while the placebo arm had almost the same mortality rate at 21% (p=0.17, not statistically significant).

There are three ways that monoclonal antibodies can be administered earlier:

1. Early treatment.  Monoclonals can be given to somebody after they test positive.  Ideally, antibodies are given as soon as possible after a positive test.
2. Post-exposure prophylaxis (PEP).  Infected individuals often continue living in their household, where they may expose their roommates/family to infection.  Those close contacts could be given monoclonal antibodies as they have a higher-than-normal chance of developing an infection.  Regeneron claims 81.4% effectiveness when its antibodies are given early to people who are at high risk of developing an infection (press release).
3. Pre-exposure prophylaxis (PrEP).  Monoclonal antibodies can be given to individuals on a regular basis.  Dosage frequency is unclear at the moment- it could be every month or as long as every 8 months depending on how long antibodies last.  Regeneron claims 81.6% effectiveness against symptomatic infection in the 2-8 months after receiving monoclonal antibodies (press release).

The current situation with the FDA and the pharma industry is a weird one.  The pharma industry sees the value of early treatment but the FDA doesn’t really want the pharma industry to go there.  The pharma companies all know that antiviral treatments work poorly when given too late.  Several months after the pandemic began, they all started doing clinical trials on early treatment, PEP, and PrEP.  However, the FDA has a bias against approving monoclonal antibodies for PrEP.  Eli Lilly has already completed a successful PrEP trial with the BLAZE-2 trial (NCT04497987), which studied prophylactic use in nursing home staff and residents.  While there is evidence that monoclonals work in healthy staff members and nursing home residents, the FDA wants to limit PrEP approval to only immunocompromised patients.  At the moment, the FDA has yet to approval any monoclonal antibody for PrEP.

The current situation is that monoclonal antibodies are severely underused because the treatment doesn’t have approval support from the FDA.  As well, the medical establishment has not been aggressive in promoting the usage of monoclonal antibodies.  Usage should still grow substantially because early treatment adoption has been rapidly increasing.  As well, Japan and the European Union had a late start in using monoclonal antibodies.

A monoclonal for pre-exposure prophylaxis (PrEP) has been commercially successful

Palivizumab (Synagis) is a monoclonal antibody designed to fight RSV (respiratory syncytial virus).  There is no vaccine available for the RSV virus as all RSV vaccine attempts have failed so far.  Palivizumab is used in babies (<=2 years old) who are at high risk of being hospitalized by a RSV infection, e.g. because they were born prematurely.  The drug is given every month for 5 months during RSV season.

Because the drug has a very small market (high-risk babies <= 2 years old), it sold $677M in 2016 (source).  The reason why I’m excited about monoclonal antibodies for COVID is because the COVID market will be massive in comparison to RSV.

• COVID-19 is generally considered to be deadlier and more impactful than RSV.
• If death is the only concern, then only about 30% of the human population is at risk of dying from COVID-19.
• If disability from COVID (and vaccine injury) is a concern, then the market is pretty much the entire human population.  (*It is possible that children don’t suffer from long COVID but I would assign a very low probability to that.)

If 100 million people in developed countries receive 2 doses a year, pharma companies will be fighting for their share of 200 million doses per year.  If each dose is $1,000, the market size would be $200B.  As stated earlier, Regeneron Pharmaceuticals has a market cap of only $69B.

Safety

Palivizumab and the monoclonal antibodies against SARS-CoV-2 don’t seem to have any safety controversies associated with them.

The adverse event reporting database VIGIAccess has statistics on Adverse Drug Reaction reports for the year 2021.  The safety of monoclonals compares favourably to other COVID treatments:

• Palivizumab – 1,026
• Casirivimab – 326
• Imdevimab – 276
• Sotrovimab – 58
• Bamlanivimab – 4,315
• Etesevimab – 493

Other COVID treatments:

• COVID-19 vaccines – 2,584,127
• Remdesivir – 2,792  (*this drug is deadly, which isn’t quite reflected in the number of ADR reports)
• Ritonavir (will be administered as part of Pfzier’s Paxlovid) – 16,274

As you can see, COVID-19 vaccines have very serious safety concerns.  Everything else looks safe by comparison.

The main safety issue with monoclonal antibodies are hypersensitivity reactions, which are basically allergic reactions.  Frequency of these reactions may be in the ballpark of 0.3-1%.  Doctors say that such reactions are treatable.

There are other monoclonal antibodies on the market that attack a specific antigen found in humans (instead of an antigen that should not be in the body).  Because they are designed to disrupt the normal functioning of the human body, they generate more side effects.  I would not generalize those side effects to the COVID-19 monoclonal.

Evolution of the SARS-CoV-2 coronavirus will likely benefit the market leaders

One major risk for monoclonal antibodies is that a single mutation can render an antibody significantly less effective or completely ineffective.  This has already happened for both antibodies produced by Eli Lilly.  Bamlanivimab plus etesevimab work poorly against the Beta and Gamma variants but do have effectiveness against the Delta variant.

A NIH webpage summarizes the current situation:

1. Regeneron and Roche have their 2-antibody cocktail (casirivimab plus imdevimab) which is effective against all variants.
2. VIR biotechnology and GSK have 1 antibody (sotrovimab) which is effective against all variants.
3. Eli Lilly has a 2-antibody cocktail (bamlanivimab plus etesevimab) which is ineffective against 2 variants.  There is a strong possibility that the new Omicron variant breaks this antibody cocktail due to its similarities to the Beta variant.

Eli Lilly’s product has been the least reliable so far.

Going forward, the best approach will be to attack with multiple antibodies.  It is unlikely that all antibodies in a particular cocktail will fail.  This quirk will likely favour Regeneron, which has the best cocktail at the moment.

Current market share

In terms of usage in the US, Regeneron’s product is leading followed by Eli Lilly.  The US government has a webpage with distribution statistics.  For the latest period reported (Nov 15-28):

1. REGEN-COV (Regeneron / Roche) – 88,692
2. bamlanivimab/etesevimab (Eli Lilly / AbCellera) – 52,474
3. sotrovimab (GSK / Vir) – 35,166

Perhaps sotrovimab should have higher market share in the US but it does not at the moment.

AstraZeneca is working on a pair of antibodies (AZD7442 / tixagevimab  + cilgavimab) that failed its STORM CHASER trial and passed its PROVENT trial.  If approved, it would be a second-tier product at best because it failed a clinical trial.

Don’t use this blog post as medical advice

I certainly don’t trust big pharma or the FDA because they covered up the safety issues with COVID-19 vaccines.  Maddie de Garay’s mother and Brianne Dressen talk about the cover-up at the 2 hour 29 minute mark of Ron Johnson’s vaccine mandates panel.  I don’t really know if the monoclonal antibody trials can be trusted.  The system is not setup to ensure that clinical trials are credible and free of manipulation.  The effectiveness numbers reported in press releases may be much higher than what will happen in the real world.

I also ignore repurposed drugs in this blog post because they aren’t commercially relevant.  Monoclonal antibodies may not be the best COVID treatment but I believe that they are the #1 treatment if we ignore repurposed drugs.  I certainly think that you should consider both monoclonal antibodies and repurposed drugs if you catch COVID.  I would also  encourage you to find a doctor who is up-to-date on COVID early treatment.

Regeneron call options are underappreciated

Regeneron and Roche share the rights to the #1 COVID drug/treatment in the world.  (The two companies “will share gross profits from worldwide sales based on a pre-specified formula, depending on the amount of manufactured product supplied by each party to the market”.)  Regeneron’s stake in REGEN-COV means that its stock has a good chance of going up several times over the next year years.

Implied volatility on the call options is in the 30s.  The calls seem extremely underpriced to me given the stock’s multi-bagger potential.  Regeneron has a $69B market cap so its options market should have decent liquidity.

 

*Disclosure:  Long REGN, REGN call options, VIR, MRNA, BNTX, and BNTX call options.