The crystal balls for 2022 and beyond..Entering inpenetrable into the brain


During the new year I guess we have to look to the future and to look in the pharma crystal ball to see what is coming your way in the near future. I have had a look at pharma’s balls.

These are called product piplelines and I have had a glance at those from the companies that make MS drugs and can see that many are testing Brutons Tyrsosine kinase inhibitors to target the B cells and also the macrophages/microglia. You know about some of them alrady and a number are in late phase trials.

There are a few T cell agents that may block B cell activation and maybe some me-toos to arrive of drugs that are similar tp already available treatments. You know what pharma is up too, not because what they tell us at ECTRIMS, it is because what they must tell their investors. They always give them the top line results long before anything gets mentioned in the scientific literature.

Some of these drugs in the pipelines probably won’t make it to the therapeutic table because they are expensive pharmaceutical turkeys and they fail the drug development pathway.

Not the image I was thinking of for a pharamaceutical turkey

One such agent seems to be opicinumab (anti-LINGO-1). This was an antibody that blocked LINGO-1, which would block (a) a biological brake to nerve regeneration and (b) a brake to remyelination.

I always had a concern about this, not because it was a useless idea, but because of the practicalities of treating brain conditions with monoclonal antibodies. About 99% to 99.9% of the antibody that gets injeted into people will never reach the brain because it is too big and water soluble to penetrate into the brain. So you have to give massive amounts to get abit of the antibody into the brain.

Oh course one can ask “Did the opicinumab trial fail because it was a mad idea to use a drug that was never going to work or was it because the antibody couldn’t get in the brain?. One way to address this idea is get more inhibitor into the brain to see if it works. So looking in the pharma crystal ball there is a small molecule drug being developed that promotes remyelination that is being tested in MS. So sounds interesting. There’s a macrophage inhibitor. Sounds interesting, there are a few others too. However before discussing them, lets wait to see if the say “Gobble Gobble.or “show me the money”

Show me the money! | Tiyce & Lawyers

The lack of antibody pentration into the brain may have also caused problems for the the Alzheimer antibody drugs.

You heard about the Do-Do trial, concept here on the blog. This was introduced with ADIOS a trial to deterimine whether 6 monthly dosing was optimal. The Do-Do trial is a DOuble Dose of ocrelizumab to try and limit progression. This came from the idea in that there is better effects on progression in smaller (lower BMI less than 25)) people compared to larger people (higher BMI more than 25). The smaller people deplete their B cells better. Is this the reason why it affects progression as it is better at stopping lesions forming or is it because a trickle more anti-CD20 antibody gets in the brain?

People are doing their best to say adios to ADIOS, although COVID-19 has given a very strong indication that it would work. But DoDo did not go extinct and was taken forward

Sol the first part of the question above gets addressed with a trial. No not by dosing to size as occurs with rituximab in arthritis but in the DODO study: (A Study to Evaluate the Efficacy, Safety and Pharmacokinetics of a Higher Dose of Ocrelizumab in Adults With Relapsing Multiple Sclerosis (RMS). NCT04544436), people will be treated with a minimum of 5 higher treatment doses (1200 mg or 1800 mg) of ocrelizumab which is double or treble the standard dosing

This is ongoing, but it looks like a lot of UK sites have been withdrawn (Based on info in clinical, and we will have to wait until 2024-2028 to get the result. It will mean that you take much longer to repopulate your B cells as you are going to add a few more months of active depletion and as for COVID-19 vacination….I think you can guess.

But this is not why I did this post. it is because they plan to address the above question another way

“Brain shuttle technology to transferAnti-CD20 antibody across the blood brain barrier and increase antibody concentrations in the brain/CNS”

Whilst searching the crystal balls I came across the claim for “Brain shuttle technology” Access of large molecules to the brain is restricted by the blood brain barrier (BBB), a gatekeeper between the blood and the brain tissue that carefully filters which molecules can enter the brain. By using the antibody engineering platform, they have created antibodies that are able to cross the blood brain barrier by binding to one of the protein receptors located on its surface. The so-called “brain shuttle” technology could potentially transport all types of therapeutic molecules into the brain. Now this idea has been discussed for many years but I am not familiar with the it actually being used.

Often the idea is to target the transferrin receptor with is an iron channel that is present on brain blood vessels. I don’t know the precise details but it is probably similar to the the technology being used for an alzheimers drug.

Have a read of this patent WO 2014/033074 Al

Hultqvist et al. Theranostics. 2017;7:308. 8D3 is used to target the antibody to the transferrin receptor

So you would take an anti-CD20 antibody and engineer it to express and antibody fragment against transferrin receptor.

Which anti-CD20 is being used? I dont know. If it is ocrelizumab we know it kills B cells by activating complement, which punches holes in the target. For this to work. Complement would have to be accumulated in the CNS. There are 9-11 components reqiired normally made in the liver. Alternatively the antibody can stimulate neutrophils or importantly natural killer cells to punch holes in CD20 positive B cells. Few neutrophils accumulate in MS lesions but you do get a few natural kille cells on MS lesions. would you want the B cells to commit cell suicide when the CD20 antibody bound to them. This may happen with ocrelizumab but this happens more with some third generation anti-CD20 antibodies.

Lets see what happens is this a game changer for antibody therapeutics

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  • What is the point of excessive anti-CD20 dosing when the challenge is to cross the BBB and wipe clean those EBV carrying mature B cells?
    Why not simply focus on this part with a small targeted dose (surgical strike as called by Collin Powell and George Bush) as an IRT, and then flush the rest of the body with any of the current agents?

    Last, do we know how well the current heavy hitters cross the BBB? Any data?

  • How long till this on market?

    MS probably won’t be the focus until all Alzheimer tests been done first?

  • Dear Barts team,

    Thanks for this post.

    In the first part of this post I get the feeling that you are not a great supporter of -mabs, am I right?

    We are using -mabs by the tens of thousands of us. Probably more.

    I was very happy with Natalizumab and when I had to stop also very happy with Ocrelizumab (back in early 2019!)

    But you suggest that all mabs only have a real small part of it that gets in to the brain. If it even gets there. Is that correct?

    I believe that most of us mabs users are pretty happy with the results, but the results can even be better when it would penetrate it to the brain. Is that correct?

    Do you know if there is/are any trials going on with nanotechnology? A Dutch chemist Prof won the nobelprize with that technology a couple of years ago. If I’m right, it can be used to transport realy small parts of meds (nano small) to wherever it needs to be.

    Thanks and regards

  • Interesting post. Thanks MD. This all sounds quite optimistic but the problem that most patients have is whether to try and ride it out until these potential game changers become available. Realistically, are they not still 5-10 years from reaching the arm (or brain) of patients. That is a lot of time in MS land and so patients are left to try and stave off the beast with the most effective poisons of HSCT and Alemtuzumab, if they can access them that is.

  • Getting antibodies into the CNS would surely be game changing if proven safe.

    Efficacy is already proven on anti CD-20 for example, so to cross the BBB could be huge.

    Then there’s other CNS diseases that would benefit

    Are there any anti bodies for plasma cells?

  • Appreciate this post MD – not exactly feels as if the world’s being set on fire tho! Is Pharma mainly focussed on simply producing variations on what is already available?

    What about the holy grail of stopping smouldering disease and restoring some of what we’ve lost thanks to this blasted disease?!?!

  • Thanks for this post. I hadn’t heard about Brain Shuttle technology, hopeful. But I have been worrying about therapeutics for Covid that might trigger a return trip…..not sure if this question even makes sense but .If A preventative monoclonal cocktail uses Fc to extend life of antibodies. Does this mean reverse transcytosis across the BBB could be triggered, and what is potential drawback for this to occur to a brain of a pwMS on DMD such as Ocrevus? (Yes I have too much time on my hands voluntarily being a hermit afraid of roaming humans and feral hogs alike )

    recently allowed for Emegency use here in States ( although supply very limited)

    • Fc silencing that extend the antibody duration as such it cant get sucked out by macrophages and neutrophils, but no the reason the antibodies cross the BBB is because it is taken through by the anti-transferrin

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