MS Octupus is hatching

M

The octupus is an incredibly intelligent mollusc and starts life as an egg. If you want to see an amazing film watch “My Octupus Teacher” its on Netflix (See trailer.https://www.youtube.com/watch?v=3s0LTDhqe5A) set in South Africa. Maybe it will be the last time you will eat one! I have seen the birth of this octupus (see below)

It is a massive (90 x 60cm) bronze made in the East End of London by an amazing artist. I first saw this a lump of clay hanging from the ceiling in the Artists studio. However, likewise I have seen the the birth of the MS octupus. This is a new trial planned for progressive MS.

Bronz e Octupus

Now you may realise that an octupus has eight arms and the first part of MS Octupus may have just four arms. Hope it doesn’t turn out to be something with 4 arms/legs.

Another of my favourite artists from Barcelona. We used to walk past the gallery every day, whilst going to an MS meeting and I fell for the beautiful flying fat lady called “Juanita Fortuna”

Octopus MS uses what’s called a multi-arm, multi-stage (MAMS) design – the first time this has even been done in MS.

MAMS trials make it possible to test new treatments up to three times faster by:

  • Testing multiple drugs at once – and comparing them with a single control group.
  • Using Magnetic resonance imaging to get an idea of whether a drug looks like it has potential, many months before we’d be able to see an effect of the drug on disability progression. Promising-looking drugs stay in the trial, with hundreds more people joining the existing participants. So what would normally be two consecutive trials are delivered in one.
  • Adding the flexibility to drop drugs that don’t look promising, and slot in new drugs as they’re discovered.  

A MAMS trial design called RECOVERY was used to find drugs that treat COVID-19. It has found a couple of drugs that worked and canned some others that didn’t. It used the power of the NHS to work as a team. Octupus MS does just this and involves a large number of people from all over the United Kingdom lead by Sir Jeremy. Theu plan to do adaptive head to head studies.

I really hope the octupus study adds agents on top of a disease modifying disease modifying treatment and look forward to seeing the trial design and the MRI outcome selected.

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MouseDoctor

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  • Presumably there are many advantages to the Octopus-design for a trial. Not least from a patient perspective, as it gets the same science done faster. Regulators will be able to see a clear comparison between currently licensed treatments and prospective new ones. And pharmaceutical companies only need to run one trial rather than several which hopefully brings prices down and saves us all a few squid… 😉

    • The Octopus trial is unlikely to result in a drug being licensed. It may give a clue to a class of drugs that work and then Pharma may take forward a new chemical entity in that class with a reasonable patent life that could pay for its development costs and the remainder of the big pharma gravy train.

    • I suspect regulators wont get involved in this too much. It costs £3,000 an hour to speak to the MHRA to get a writtne response and about £33,000 an hour for the EMA. They (MHRA) do it for free for academics I have been there twice.
      They are only interested in safety and cost does not concern them. However steroids were approved for use in severe COVID-19 so this is the model that needs to be followed for Octopus.

      “Pharmaceutical companies only need to run one trial rather than several which hopefully brings prices down and saves us all a few squid”…If we get a neuroprotective, remapir agent costing a few pennies then pharma will be off. I learned this from trying to develop a symptomatic agent and the investors said you hhave baclofen costing pennies you won’t get thousands for a new agent and without that we wont invest in the trial.

  • Honestly, the biggest issue is the 3 stage trial design. While I understand safety issues, drug repurposing could really expedite the process. But a few questions come to mind but mainly, what’s the drug selection criteria? I remember the clemastine trial used under the microscope cell maturation.

  • Good morning MD what a brilliant post on all counts 😊 My Octopus Teacher is a beautifully made film and opened my eyes to what amazing creatures octopus are.
    Each sucker individually controlled with a CNS in each arm. 8 arms and 9 brains! Spoiler:when an arm is injured or lost it regrows perfectly so don’t be too frightened in the chase scene. Pity neuroregeneration not so easy for us.

    Octopus is a very appropriate name for the MS Society platform… we all look forward to trials getting underway soon.

    I love that Octopus sculpture, stunning!

    • Hopefully profG got to seee the film, set on the Cape. In the UK the Octupus has special protection in terms of research I learned abit about life span

      Sculpture…Andrejz is super talented artist. The octupus has a beak. Maybe for Q & A, I will ditch the flowers and his Fish, the octupus was way too big. In my third year General Zoology exam be had a practical test…There were skulls that you had to identify e.g. a marsupial skull can be identified by a number of distinguishing features. There was a picture of a Friesen cow and badger in another test…Not sure the answer was they are both black and white maybe something to do with tuberculosis? then we had an octupus beak..I will never forget someone said it was a wood boring beetle :-). It did not have six legs for a start. It was a hard exam written exam too. e.g. A pterodtyl is like a hang glider discuss.

  • Haven’t we been here before with the MS Smart trial? In that trial all 3 promising agents failed and MD1 (after the results were published) criticised the trial design etc. Couldn’t MD1 sit on the steering group for Octopus to ensure lessons from past failed trials have been taken on board? Couldn’t Prof G push for an anti-viral (or possibly HAART) to be one of the agents tested? We really need to be addressing the viral hypothesis and piggy backing on the MS Society funded Octopus trial would be an efficient way of doing this.

    • So I throw this back to you SID. why don’t you get on the PPI committees and research network and drive these questions to be answered? The MS Socieies respond to the power of the members, otherwise the canadian and Italina MS Societies would not have poured millions done the drain on CCSVI. I would say many people do not have ProfGs passion and they think the viral idea is a pile of old cobblers. The raltegrivir trial went down in flames, vitamin D has not a major impact etc.

      Maybe pharma will come to the show and use the platform, but history shows they do not like to lose control. Others ask if you show a positive effect with an agent then what?

      However first to address your point
      (i) You do not ask to go on committees, you (ii) are asked to go on committee. Unless you are (iii) in the inner sanctum you don’t know about the comittees until after they are formed. (iv) Then it may be too late to get asked on to the committee. I was asked to go on a drug selection committee. I dont think anti-virals got much of a look in…

      I think you are correct this sounds like MS-SMART2….but MS-MSART was not so smart as it picked losers, but here the vision is to have a constant cycling of candidates as one drops out another goes in. This approach could be a bottomless pit as it sucks in resource. Being in a trial is beneficical even if you get placebo. The design was pioneered in Cancer and this person is involved in this study. ProfK and ProfB met them when looking a cladribine development. There’s a story, but what happened in the MRC stays in the MRC:-). Sir Jeremy has a track record of co-ordinating National Studies.

      However the whole approach is a battle and a balance…The unmet need is in late progressive MS, but the best way to show neuroprotection in my mind is in early MS. PPI wants the Former…what is going to happen? In MS-SMART they argue that they picked Ibudilast. I was critical of the drug selection approach for MS-SMART as the animal model was an essentail part on the selection process and EAE was never going to properly inform. Octupus is based on repursing drugs and picking biological processes. It is laid out in Cunniffe et al. 2020/2021.https://jnnp.bmj.com/content/jnnp/92/3/295.full.pdf

      To address your point there were two major arms one was to identify agents (Lead by Prof Coles, Cambridge) and the other is trial design lead by (Prof Chandran, Edinburgh) but in reality this is a three committee approach one on design, one on outcome and one on infrastructure. The chairs were not going to be recipients of any funding. The drug selection approach was published on Cunniffe et al. 2021 and ProfB and ProfG were on that committee….. I spent alot of time doing work on drug selection and they were all thrown out. Where majority rules a lone voice gets no where. Furthermore, a pain in the arse…gets removed from the process/side-lined. I have repeatedly said without an effective trial design, it doesn’t matter what you pick. What is the Imaging outcome that is robust for clinical trials.

      I said this to the Progressive Alliance and I have said this here too. I have also repeatedly said that you should not do a monotherapy but you need layering. I am only hopeful that with the advent of agents for PPMS and RRMS this will happen. I can take no credit for the final drug selection as I was not there when the decisions happened (See maybe they thought I was an arse-hole also). It is always difficult to get every body in the room at any one time.

      Did I disaggree with the final choice, not really you have to make a start. Did I disagree with some of the choices? I would have picked others. As for the trial design this is a differnt committee again. A voice of a scientist against a group of neuros will not get anywhere. (They may see yes, yes yes in that humouring type of way and 5 mins after you have gone they forget about what you said).

      Maybe they put ProfG in the treatment selection group to keep him away from trial design:-)

      As for HAART, surely if profG believes it is the way to go, then this should be a separate application. The worst thing as a scientists is to see all your hard work and dreams being shattered by someone else doing a trial. The cannabinoid approach in my opinion killed the approach due to the trial result.

      • Thanks for the detailed response. Have a pint on the 12 April (in a pub garden) by the river Lea and I’ll send you a postal order to cover the cost.

      • Re
        The unmet need is in late progressive MS, but the best way to show neuroprotection in my mind is in early MS. PPI wants the Former…

        You’re right of course MD. Problem is pwMS who’ve missed out on effective treatments in early MS are here today and getting worse… and they’re the ones with time free to take part in PPI.

        But I agree, neuroprotective drug should be started at same time as first anti inflammatory dmt.

        • But if a trial in later progressive will take 5 years to get an answer and the early a couple of years. PROXIMUS should be repeated it could be done off label…will it every get done? Not without MoJo

          • Oxcarbazepine is still on the Octopus list so if any new evidence was to surface to back it up you never know…

            Why didn’t PROXIMUS show anything? Nfl wrong endpoint? What if looked at brain volume over 2 years like STAT1?

          • That is because we tried to put it there but until PROXIMUS is repeated and published no one will buy it. However, Nfl was wrong endpoint because once you take the inflamation out of the equation the effects are too small…it is a marker of active lesions. MRI was not useful either….which is the same conclusion in ibudilast no effect on atrophy or neurofilament….the odd thing was there was a positive clinical effect, so why bother with imaging and neurofilament, repeat the study and see if it was a fluke, it could have been done by now.

  • I think haart is a great idea for a separate trial have you thought about going to see a major news station and telling the ebv story ? This way other people would also find it worthwhile as an idea to be explored and then ms societies would have additional pressure to take these things seriously ?

    Just like the news station sold and amplified the story of getting a surgery for the artery in your neck to cure ms. This time it would be used for a good idea. It would need to be a news station that can reach thousands if not hundreds of thousand of people. Prof G and david baker together and whoever else would want to join in could make that interview a reality by showing multiple experts agree on this.

    You could mention atarabiotherapeutics, you could mention moderna has mentioned that their is a lifetime increased risk of multiple sclerosis as well as the graphic they are using showing that if you are ebv negative your risk of ms is pretty much close to 0. Moderna mentionned all of this in their pdf file of their ebv vaccine. Therefore making your arguments that much stronger in the news station.

    • If we had the ears of the media it would be easier
      You also have to careful you dont sound like a mouthpiee for ATARA and moderna

      • Well I am sure one or two journalist have some sort of connection to multiple sclerosis I am sure there is someone that would be interested to listen to both of you and make a story about it.

        If I try to help find that contact would you be interested ?

        I would help find the best possible match but I would let you reach out to them. If you are interested, I will do my own homework and give you a few options as to who I think could be interested in listening to both of you based on a few criteria that I will explain in more detail once I have a few candidates to give you. There is no guarantee but I will try to maximise our chances. Would you be interested in seeing who I could find for both of you ?

      • Anyone thought of contacting Caroline Wyatt? May be a way to get a champion in the media, just an idea.

  • If pharma does not jump on board what do we do with the identified drugs? Fight for Off label use? Why we see papers on drugs that had great results on few people and these are not replicated? I am thinking to the Rejdak paper on cladribine and ocb or to the combivir case… there are thousands of people on clad why this study is not being replicated to build a solid base to see what ocb are doing? The combivir story have amazing results… why nobody replicated it? Then why this its do hard to do even if preliminary info are available?
    I fear we will end up with just a list on the wall 🙁

  • I don’t believe my slow PPMS has much to do with my immune system. EBV is where it’s at IMHO. I’m certainly not interested in anti-inflammatories and complex add on drug cocktails.

    Octopus is not for eating. Totally unnecessary.

  • Dear Sir/Madam
    I have secondary progressive MS and I have been reading about the MS Octopus initiative. I am interested in going on the trial and would like to know what it involves. Could you please let me know what is required for me to go on this trial.

    I hope to hear from you soon.

    With regards

    Miss Tijen Orman

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