66 Comments
Apr 18, 2023Liked by Gavin Giovannoni

Simple question Prof....if you had MS, which would you take? reading this would suggest ocrelizumab due to its greater impact on smouldering MS. This could be confusing given the higher score assigned to ofatumumab on the selfie cards. I know you would have Lemtrada or HSCT but i am afraid they are not available to you in this scenario ;-) ......rubbish isnt it

Expand full comment
author

Alemtuzumab or AHSCT ;-)

Expand full comment

But 'oneinthree' raises a salient point... these two treatments are not available for the vast majority of us*! A good idea for a future MS-Selfie would be comparing the 'accessible' highly effective therapies with regard to smouldering MS... I saw Dr Boster's recent vid rating the DMTs, in which he placed ocrelizumab above natalizumab (which surprised me) - would be very interested to hear your take on it too.

*I asked about alemtuzumab in March 2021 - was told my trust had discontinued it for safety profile reasons. And although I'd read about STAR-MS being in development, given I was relapsing every 2/3 months, I felt I didn't have the luxury of time to ask to be put on a waiting list for that...

Expand full comment
author

At present the data on smouldering MS has to be based on the impact of these therapies on brain volume loss. The latter is a mine field as it is impacted by age, disease duration and when treatments are started. At present the best data on reducing or pseudo-normalising brain volume loss is for AHSCT and alemtuzumab, followed by natalizumab, then ocrelizumab, then the S1P modulators, ofatumumab, teriflunomide, cladribine, IM interferon-beta-1a (Avonex), .....

Expand full comment
May 27, 2023Liked by Gavin Giovannoni

Hi Gavin, interesting that you rank natalizumab 3rd - as I understand it natalizumab does not enter the CNS - which is what you said was needed to impact the smouldering MS? Ps Subscription is worth every cent! Thank you!

Expand full comment
author

The ranking is based on brain volume loss after rebaselining at 12 months. On natalizumab the average BVL is in the region of 0.25% compared to 0.15% or lower on AHSCT and Alemtuzumab.

Expand full comment
May 27, 2023Liked by Gavin Giovannoni

Thank you for replying. I actually was wondering why you didn’t pick Ocrelizumab as 3rd but I presume the data for bvl isn’t as good? In the podcast you say you need the medication to enter the CNS like a B cell depleter. I wonder why natalizumab is superior in bvl if it doesn’t enter the CNS? Thank you again!

Expand full comment

Thank you, that's an insightful response.

Expand full comment
Apr 18, 2023Liked by Gavin Giovannoni

This is a fantastic summary (Altho I also feel the info cards are misleading). I’m not sure about whether your neurology consultant colleagues across the country are in agreement with you however. I do wish there could be more consensus/transparency. It makes decision making as a pwMS incredibly hard.

Expand full comment

I wondered why ofatumumab had scored so highly on the MS Selfie cards.

So it's low dose convenience (and questionable improved safety) versus high dose infusions and better long term outcomes. Hopefully

NCT04544436 will tell more. When might this be?

Expand full comment
author

Spot on. I assume the Newsletter is understandable? The point I am making is that we should not get too worked up over relapses and MRI activity and focus on disability progression and more importantly brain volume loss. If you do this across all DMTs then alemtuzumab and AHSCT win hands down.

Expand full comment
Apr 18, 2023Liked by Gavin Giovannoni

Perhaps if the MS selfie cards are misleading people in favor of kesimpta over ocrevus based on the relapse ratings this should be addressed. If the difference is likely clinically insignificant would it be an option to rate the drugs the same for relapse thus allowing people to have a further discussion with their team regarding the nuances? Not everyone will have the benefit of reading this article when making a decision and may misunderstand the ratings.

Expand full comment

Exactly! Newsletter very understandable thank you. Still puzzled why ofatumumab was up there (almost) as good as alemtuzumab and HSCT on the MS Selfie score cards!

Expand full comment
founding
Apr 23, 2023Liked by Gavin Giovannoni

What are your thoughts about Ibudilast? It was shown in Phase 2 trial to slow brain atrophy for PPMS by almost 50%? It has not progressed to Phase 3 although recently, Iranian scientists (Dr Varshosaz) have found a more effective way to administer Ibudilast via a nasal spray.

Expand full comment
author

Ibudilast needs a phase 3 study. Without it it remains another promising therapy on the shelf because there is no new IP to protect it. Without a return on investment no Pharma company will invest in a phase 3 programme.

Expand full comment
founding

Such a pity cos the stats are good for smouldering PPMS. Anything the wider community can do to move it along? Even FDA was willing to give it fast track status.

Expand full comment
founding

What about Octopus trial?

Expand full comment
Apr 19, 2023Liked by Gavin Giovannoni

Quick question and a bit off topic ,I saw on social media groups regarding Ocrevus and JC virus testing

Someone mentioned they are transitioning from ocrevus to Tysabri and that they’ve been told the JC virus test won’t be accurate as they have been on ocrevus. I’ve never heard of this before?

Expand full comment
author

Yes, that is correct. You can only use positive or negative JCV status and not the index as ocrelizumab or anti-CD20 therapy blunts antibody responses and makes the index unreliable.

Expand full comment

Is that why Tysabri to ocrevus is the safer way of switching

So if someone does it the other way around they are relying on being negative or positive. Pretty big risk of the index is unreliable

On the topic I’m personally more inclined to go cladribine after Tysabri due to vaccine response. With covid, future pandemics, mosquito borne viruses I’m weary of constant b cell depletion and limited vaccine response. In australia we finally got Japanese encephalitis and I was able to get vaccinated but would worry with a b cell depleters.

Expand full comment
Apr 18, 2023Liked by Gavin Giovannoni

Interesting, informative and well-argued, thank you!

Expand full comment
Apr 18, 2023Liked by Gavin Giovannoni

Thank you very much Prof G - very interesting and particularly personal to me too! I look forward to hearing about the trials and for the record, I would like to have both brain and disability progression stopped - so I’m all for the higher dose, to achieve this. All the best :)

Expand full comment
Sep 6Liked by Gavin Giovannoni

Thank you, What do you think about sucutsnous ocrevus. Do you think the old classic Infusion is more effektive regarding zns penetrance or do you the sucutsnous and intravenous ocrevus is no difference ? Thanks for your thoughts because my doc told me i should choose one for the next time. Its my 3 rd time to Recieve ocrevus at all.

Best regards and Thanks from Germany !!

Expand full comment
author

There is no major difference between the two formulations of ocrelizumab. However, the subcutaneous formulation is really an infusion and not an injection. It takes longer to be administered than an injection. It is horses for courses. The cynic in me says Roche developed and launched this product to extend the patent so there will be a push to convert as many pwMS as possible to the sc infusion before ocrelizumab biosimilars arrive.

Expand full comment
Aug 24Liked by Gavin Giovannoni

Dear Prof G, does it make Sense to take vacinations under ocrelizumab or dont vacines work under ocrevus treatment ? Ne last Dose of ocrevus was on 2th of may. So nearly 4 month ago. When is the best time to take vactination between the next Infusion Interval? I Need the vscinations for travelling reasons . Thanks for your help!!

Expand full comment
author

Yes, you still should have vaccines and vaccine boosters the exception being live vaccines. Anti-CD20 therapies blunt B-cell or antibody responses not T-cell responses.

Expand full comment
Apr 5Liked by Gavin Giovannoni

Dear Prof G, did i unterstand right that ocrevus seems to be stronger than Kesimpta ? Thank you !

Expand full comment
author

Yes. It is a more potent B cell depleter. It takes longer for your B cells to repopulate post ocrelizumab compared to ofatumumab. Higher doses of ocrelizumab may also result in more CNS penetration which may be important as well.

Expand full comment
Apr 5Liked by Gavin Giovannoni

Thank you so much for your quick answer. But you still recommend Cladribin more , Right ? :)

Expand full comment
author

No, not necessarily. It is horses for courses and everyone needs to choose their own DMT based on many different factors. For example, at present the criteria for starting ocrelizumab and cladribine on the NHS are different. So you may be ineligible for cladribine and still be eligible for ocrelizumab.

Expand full comment
Apr 22, 2023Liked by Gavin Giovannoni

I switched from ocrelizumab to ofatumumab after I stopped ocrelizumab to to to get a response to the Covid vaccine. Restarted with ofatumumab due to better B-cell recovery times. I've never had a relapse so that data doesn't really speak to me -- my MS has likely been around for a long time slowly causing damage (only dx 5 yrs ago). End-organ damage data really does speak to me, as I can really see the deterioration for myself. I can't get coverage for HSCT or Lemtrada, and it looks like my new insurance would prefer me to do ocrelizumab to ofatumumab, so maybe I'll switch back. But I am wondering when it may be time for me to just stop DMTs as the ROI is really looking increasingly questionable.

Expand full comment
author

I think you still need an anti-inflammatory and to build on that with future therapies.

Expand full comment
Apr 20, 2023Liked by Gavin Giovannoni

Thank you for this article.

Expand full comment
founding
Apr 19, 2023Liked by Gavin Giovannoni

If you were just diagnosed with PPMS at 54 years old, what would u choose? AHSCT? Ocrelizumab? Alemtuzumab is not recommended for PPMS?

Expand full comment
author

Ocrelizumab. It is the only licensed therapy that is available for active PPMS in the NHS. AHSCT is not available because we don't have enough data in treating pwPPMS.

Expand full comment
founding

Thank you for your prompt reply and your passion in helping MS patients. We so need doctors like you. Have you in your experience found ocrelizumab to work for PPMS?

There has been research from Tisch MS centre and university of colorado (Xiaoli Yu) that antibodies in CSF of PPMS patients in particular are pathogenic. I hope there will be more research on this to find an effective treatment for smouldering MS.

Expand full comment
Apr 19, 2023Liked by Gavin Giovannoni

Thank you for the article prof G.

Ofatumumab is not available in my country anyway...

Expand full comment
Apr 19, 2023·edited Apr 19, 2023Liked by Gavin Giovannoni

You only touch on it briefly, but given we still live in a COVID world, for some it is still important to take into consideration the need to take vaccines, and to enable them to be effective when on an anti-CD20 therapy that depletes B-cells.

PwMS with a stable disease condition, no brain volume loss or increased disability, may not need to be taking high doses. And as you point out these doses are typically all the same despite the fact people are not and their needs are not.

What I would like to see are more studies around the dose levels. I feel that the process of getting a drug approved makes it less likely than not that resources are not available to analyze different dosing levels.

One thing with ofatumumab is that one can more easily adjust down the dose by taking it less frequently. That's at least something, even if it means a lower, not higher dose. It is what I myself have done for the past two years without feeling or seeing any negative effect of having done so.

Either way, your article is interesting.

Expand full comment
author

Re: "resources are not available to analyze different dosing levels"

Not quite true. Roche/Genentech are spending vast sums of money testing 600 mg vs.1200 mg vs. 1800 mg of ocrelizumab based on body size. Other countries are testing rituximab vs. ocrelizumab. It is important the the outcome is not simply relapses and/or MRI activity (NEIDA), but they go beyond that and look at disability progression and brain volume loss, i.e. smouldering MS.

Expand full comment
Apr 19, 2023Liked by Gavin Giovannoni

Good to hear. Anything of that sort going on with Novartis?

Expand full comment
author

Not that I am aware of.

Expand full comment
author

Re: ".. without feeling or seeing any negative effect of having done so.."

The problem with this is that unless you look beneath the surface you have no idea what MS is doing. A lot of smouldering MS disease activity occurs without causing symptoms until it is too late and reserve capacity has been reduced to a point were the brain and spinal cord cannot compensate for any additional damage.

Expand full comment
Apr 19, 2023·edited Apr 20, 2023

In my particular case I do that yearly. So far so good since I've been on Kesimpta.

Expand full comment

How do you monitor this yearly? Are you doing this in the UK? Thanks

Expand full comment

I am in the US. I have yearly MRIs. At the beginning of the COVID vaccine rollout, I also had regular blood lab tests. Based on these I have modulated my therapy.

Expand full comment

We have yearly MRIs here too (UK) but I’m not aware what can be determined from a blood test - can you tell me? Thanks!

Expand full comment

Sure. The blood tests gave me B-cell counts and anti-body counts, allowing me to track my depletion levels, and identify whether my COVID shots were effective. From them I could get a better picture of how long it took for my B-cell levels to bounce back during my breaks from taking Kesimpta, get a better sense of how long I needed to wait before taking a vaccination shot, whether my second COVID shot was effective, whether the booster was effective, and so on.

The MRIs could be analyzed for new lesions, and brain volume loss.

Expand full comment

We also IMO need more inactive vaccines.

MMR as a big one. I had done the serology and started Tysabri but we found out I had zero immunity to mumps. This isn’t unheard of but I can’t now get a booster due to live vaccine

We need better vaccines and non live versions as well

Expand full comment
Apr 18, 2023Liked by Gavin Giovannoni

Thank you Prof G. You mention BTK Inhibitors in your article. Is the Tolebrutinib trial currently recruiting for progressive patients in the UK or is it still on hold? Also, do you think your Sizomus trial in London will become available in other parts of the country?

Expand full comment
author

Re: "Tolebrutinib trial currently recruiting for progressive patients in the UK or is it still on hold.."

Yes, it is we are a site. It was only paused in the USA by the FDA.

Expand full comment