Is it underdosed?


ProfG has got his way and a double dose of ocrelizumab is going to be trialled. He has wondered whether the dose of oral cladribine is optimum. In the phase III clarity trial 3.5mg/kg and 5.25mg/kg were tested and were pretty similar, but the higher dose had more adverse events…but one of those that caught the regulators eye was lymphopenia, which is a mechanism of action. The dose was adjusted to avoid lymphopenia. Therefore, one wondered if one was diluting the effect away. It seems that it can deplete B cells as well as alemtuzumab and ocrelizumab and depletes T cells better than ocrelizumab but natalizumab is continuously given and will target T, B and monocytes. In this study supported by the makers of cladribine, they tried to do a virtual head to head studies and it argues that it is similar to fingolimod better and not as good as natalizumab.

Signori A, Saccà F, Lanzillo R, et al. Cladribine vs other drugs in MS: Merging randomized trial with real-life data. Neurol Neuroimmunol Neuroinflamm. 2020;7(6):e878. doi:10.1212/NXI.0000000000000878

Objective: Cladribine tablets were tested against placebo in randomized controlled trials (RCTs). In this study, the effectiveness of cladribine vs other approved drugs in patients with relapsing-remitting MS (RRMS) was compared by matching RCT to observational data.

Methods: Data from the pivotal trial assessing cladribine tablets vs placebo (CLARITY) were propensity score matched to data from the Italian multicenter database i-MuST. This database included 3,150 patients diagnosed between 2010 and 2018 at 24 Italian MS centers who started a disease-modifying drug. The annualized relapse rate (ARR) over 2 years from treatment start and the 24-week confirmed disability progression were compared between patients treated with cladribine and other approved drugs (interferon, glatiramer acetate, fingolimod, natalizumab, and dimethyl fumarate), with comparisons with placebo as a reference. Treatment effects were estimated by the inverse probability weighting negative binomial regression model for ARR and Cox model for disability progression. The treatment effect has also been evaluated according to baseline disease activity.

Results: All weighted baseline characteristics were well balanced between groups. All drugs tested had an effect vs placebo close to that detected in the RCT. Patients treated with cladribine had a significantly lower ARR compared with interferon (relapse ratio [RR] = 0.48; p < 0.001), glatiramer acetate (RR = 0.49; p < 0.001), and dimethyl fumarate (RR = 0.6; p = 0.001); a similar ARR to that with fingolimod (RR = 0.74; p = 0.24); and a significantly higher ARR than natalizumab (RR = 2.13; p = 0.014), confirming results obtained by indirect treatment comparisons from RCTs (network meta-analyses). The relative effect of cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years) was higher in patients with high disease activity vs all treatments except fingolimod and natalizumab. Effects on disability progression were largely nonsignificant, probably due to lack of power for such analysis.

Conclusion: In patients with RRMS, cladribine tablets showed lower ARR compared with matched patients who started interferon, glatiramer acetate, or dimethyl fumarate; was similar to fingolimod; and was higher than natalizumab. The beneficial effect of cladribine tablets was generally amplified in the subgroup of patients with high disease activity.

Will we ever get real head to heads. This will be the way

COI> Multiple

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  • MD,

    Thank you for a non-Covid 19 MS post. Hopefully we will see more of these with the ACTRIMS/ECTRIMS virtual conference at the end of week.

    Prof G appears to have gone AWOL. In the past, he has posted many times his view that MS is not relapses or MRI activity. In his view the real MS is smouldering MS and relapses / focal inflammation are the immune system’s response [I’m happy to be corrected, but this is what I think Prof G has been suggesting].

    Given this, will the DODO trial (double dose of ocrelizumab) be seeking to address the real MS? Ocrelizumab has already shown that it is highly effective at addressing relapses and focal inflammation. How will the DODO trial show that double dosing will have an impact on the real MS (smouldering MS)?

    Thanks for all your work on the blog.

    • Dodo study will be a success if high dose of anti cd20 show less progression (especially PIRA) and less end organ damages.

    • It may enter the MS and block B cel activity there reducing the the trophic support for the B cell folliclea that product the antibody that activates the FGc receptor of the microglia and therefore creates a reduced neurotoxic environment and the real MS smoulders less….for example

  • I’ve wanted to see head to head studies ever since I was diagnosed. My current neurologist is disgusted that there aren’t any too. I asked why there aren’t any, she said that she’s it’s about money.

  • I would love to know. First year of cladribine, felt marginally better. 3 months after year 2 cladribine brain fog is 90% better, fatigue and jello legs 90% better, heat sensitivity 50% better, hope they will keep getting better, but would love to know what would have happened if dose was higher or 3rd year available.

  • Anyway following up on the first post, I guess I’m going to change to Lemtrada. I started with Tysabri, didn’t have any relapses for 2 years. Then JCV levels suddenly went from 0 to over around 4. Then, I had Gilenya kinda pushed on me 🙄. Relapsed on that about 9 months after starting.

    The relapse felt relatively mild compared to others and my disability levels went back to where they were after a round of solumedrol. But I was left with a large lesion close to my brainstorm. 2 neurologists were very alarmed. So on to Ocrevus.

    Had 3rd infusion of that in June. Now I’m relapsing hard. It’s been going for over a month despite solumedrol infusions. So now I’m gonna change to Lemtrada as soon as I can. I wanted that in the beginning but the neurologist emphasized the risks and didn’t want me to do that. She would’ve done it if I’d insisted. I wish that I had 🙇🏻‍♀️

    I know that ya think that B cells are the bad boys. I just can’t understand why I did so well on the T cell killer. Ocrevus hasn’t been at all successful, Plus, I weigh under 100 pounds, the regular doses that I’ve had were pretty high for my weight, definitely not under dosed.

    I think that the only reason that infusions after the first one, which left me really sick for weeks, were better was because they ran it really slowly. My mother’s a nurse and stayed with me while I was knocked out from Benadryl and reminded the infusion nurses that it’d been written in the order that they had to keep it slow. And neuro ordered an additional bag of saline afterwards, maybe that helped but I don’t know 🤷🏻‍♀️

    • Thanks for your story. Often the first set of infusions with ocrelizumab are the worse, possibly because you are depleting B cells and they are gone for the subsequent infusions. Some neuros asked me about disease re-activation after rituximab and I have to build these events into my story, accepting that no treatment behaves perfectly

      • Thanks for all that you do, and for offering so much information! I had expected the half doses to be bad, but not that bad lol. My legs hurt so badly that I cried for days. I’m not a baby, I have a crazy high pain tolerance, but wow! I actually had a baby with no medication, and that dose was a lot worse. I drank so much water to try and flush out my system and then crawled, sobbing to the toilet.

        About disease ractivation after rituximab- I’m really, really glad that you brought that up. I guess I’m going to have to wait for B cells to go up before starting Lemtrada. Do a lot of people have severe rebound activity when they stop taking rituximab?

        I had to change from Gilenya to Ocrevus shortly after the FDA issued their report about severe disease activity after stopping that. So neurologist had me keep taking Gilenya as normal until the night before I started Ocrevus. That might have been a part of what made the first dose so bad?

        Anyway, I am worried that it might take a long time for my B cells to go up enough to start Lemtrada. My EDSS was already 5-5.5 before this relapse from hell. I think that it will be higher when it ends. I’ve only gotten back to my pre-relapse disability level 3 or 4 times after a bad relapse. I was 26 when I had the first one, if that matters.

        At the end of every day, I wish so much that I could afford to head to another country for HSCT. I actually asked my first neurologist what he thought of that idea the last time I saw him before I moved across the country. I’d looked up information and knew that the year before, he’d been paid almost by $200,000.00 by Biogen for doing promotional crap. So I expected that he’d be against it, even though I thought (and still think) that he’s a very good neurologist.

        He wasn’t against that at all. Actually got pretty excited talking about it lol. He told me that he was glad that I was considering that. That he would be behind me if I did it. He just wanted me to be very careful in choosing a reputable facility. He said that he was 100% sure that it would be FDA approved eventually, but it would probably take at least 5-10 years. That I shouldn’t wait for that to happen. He told me that if I found a way to pay for it, that I should do it as soon as I could. I really wish that I could.

        Anyway, I’m sorry for this really long post ☹️ I’m just really worried that I’ll get a lot worse while I’m waiting to start Lemtrada.

        Have you seen or heard about anything that is used with any degree of success to prevent that from happening?

        • I dont think that your advisor has sipped from the pharma cup amounts to much, they are all pharma whores and have lips like a shoveller (a duck with big Fing lips@:-)
          and will do the stuff they are asked to do..Hey I would be a Ho too if I can get the gig ,it doesnt mean that they are not willing to stand up againt their sponsors, but I am alays willing to help whee ever I can, If I can can get paid of this…great. If not no problem. Some people are risk adverse and so are some neuros. If your neuro is one of those people you get offred a CRAB and they SH1 themselves if they have to prescribe away from that.

        • just so you know the $200,000 isnt in the pocket,

          I think I know who you are talkg about. In the US they have become transparent, not so in the UK yet. If you fly to the USA from the UK that is $7,500 that goes into your kitty. Nothing in my pocket. Have a burger and that is in your kitty.

          Companies have to fly you business class if the distance is over a few thouand miles. Prof G is 6 foot and alot and get leg cramps from being in shitty coach, and so a business class bed is great. I have little legs and fit in the crappy seats. However I love the business class bed and doing a 5,000 mile compute to work is pretty cool.

          I went to Australia, I picked the flight so that I would leave at midnight on saturday, I went into the business class lounge drank, way, way too much in the business lounge and then fell asleep for 10hours woke up in singapore feeling great and relaxed, hit the bar and had a an 8 hour sleep arrived in Oz on monday a 5.00 am feeling great. On the way back left at 10 from Syndey drinking class to signapore, 50minute layover and heavy sleep for 12 hours and straight into work. On another occassion one friday I flew at 5.00ppm to lisbon portugal, watched football and got at midnight flew to Rio. I arrived a 5.00 am did 6 hours of talks and left at 10 pm on saturday night, arrive home sunday afternoon…I got 10,000 airmiles, a few bob, no time off work and probably about $15,000 as a pharma cost . I wish I had the cash I also wish I had gone to Rio as I went to the bay next door. It was so cloudy i thought the sugar loaf mountain was infront of me it wasn’t.

          I guess post covid those days are over.:-(

          • Lol. I don’t hold it against him. In his case though, I’m pretty sure that he was directly paid. Almost all of the speaking engagements and promotional events that he was compensated for were in the city we both lived in, so at least he didn’t have travel expenses 😎.

    • Amy, I hope you improve real soon, easy for all of us to second guess the choices. Stay Strong. The powers to be really don’t help us pick the best drug of choice because of all the non-sense and bureaucracy. However, You hit the nail on the head, does anyone know for sure what is happening to pwMS and how to treat properly, still waiting for the MS cause or causes. MS is a tricky evil, I wish we would find our way, MS is desperate for a serendipity moment BIG TIME or is the problem too complicated to solve. My gut feeling says, Could one of the main MS culprits be the 2,000 nuclear explosions polluting the planet since 1945 equalling 30,000 Hiroshima’s. My family lived in New Mexico(NM) since 1890’s, they were exposed to the downwind radiation from the first atomic test in 1945, and they ate contaminated food, breathed the toxic air, and played in the fallout. They didn’t inform 560,000 plus people of the radiation danger for 3 weeks after the explosion that spewed radiation in every direction and then down played the risks to this date, war collateral. Now we know the worse Fallout moved toward us. The majority of us display neurological problems and/or immune system disorders for example Dementia, Parkinson’s, MS, Cancers, and the unknown DNA damage the powers to be downplay. My Father/Mother were 3 and 1 y/o after the explosion in 1945. Could the increase in Cancers and Neurological problems be as simple as exposures to man-made accumulation of high/low dose radiation in vitro or post birth over the decades. My Mom is dead at 59 from MS complications and my father has early onset of Dementia/prostate cancer survivor. Radiated again in NM from the 1960 Nevada nuclear tests, then add other leaks of radiation and dangerous metal poison leeching into the ground water via the Pantex Plant in Amarillo, TX (SuperFund site). Triple play of radiation death is the title of my short life story, if I live long enough to write the story. Interesting story unless you are living the nightmares. My gut feeling may be correct, no one in the previous generations can equal the death and destruction post 1945 explosion. We are the first atomic bomb victims, we have been forgotten by our own government, the 75th anniversary of the First Atomic Bomb July 16, 1945.

    • Amy, I started with Gilenya in 2013 for 2 months, then shingles and other side effects. Next, I infused Tysabri monthly for 6 years until work stress/JCV titers trended up, then we decided to go with Lemtrada. I was leaning toward Ocrevus, however my MS Dr thought I would fair better on Lemtrada per my MS. She may be correct, I haven’t declined after completing Lemtrada rd 2 last June 2020, however, I haven’t reached the energy levels or the levels of ability prior to Lemtrada. I hit a wall, cramp up, or too tired to keep going these days, possibly the cooler weather coming soon will invigorate my soul.

      • Mars, I really hope that it does end up helping you more. Do you think that you might do a third round? A woman I met right after we were both diagnosed was about my age. We were both at similar levels of disability. She was on tysabri for about 6 months before she went to an MS clinic in another state. The neurologist who saw her there had her start Lemtrada within a few months.
        She questioned her decision when she had a severe relapse 4 or 5 months after having the second round. I’d moved away by then, but felt so bad for her. She didn’t bounce back from that very well at all and was left having a few pretty bad new symptoms. She decided that she’d go ahead and have a third round since she’d already been through so much and didn’t think that she had much to lose 🙁
        Surprisingly for both of us, that third round seems to have made a huge difference for her. Some of the worst ones that she’d had since before being diagnosed , plus new ones that she’d been stuck with actually improved a lot within months.
        The thing that scares me about Lemtrada is that my current neurologist gives a very strong impression that she considers it to be a last ditch effort. The potential side effects seem to make her hesitant in prescribing it. She doesn’t think that there is anything else that comes close to being as effective as Lemtrada is left to try if it’s a major failure. It upsets me if I let myself wonder about what the heck I’ll do if it makes me worse 🙁

  • “but one of those that caught the regulators eye was lymphopenia, which is a mechanism of action. The dose was adjusted to avoid lymphopenia.”

    So can you check if patients on Cladribine that DID experience lymphopenia are better off than those that didn’t deplete so much? We know that people deplete differently on Cladribine, even if they are put on a weight adjusted dose. Some simply deplete really hard, and some not so much on the same dose.

    So what I’m asking is: because depletion is measurable, can this be taken as a prediction of the efficacy and prognosis?

  • Interesting. My Nuero gives me a half dose of Ocre (300) because I am tiny (95 lbs). Same amount of Steroid/Benadryl though.

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