I must have Wind as it seems I keep repeating myself

I

Todays B cell burp was reported as it came out of the Horse’s mouth when it came out at ECTRIMS2019, so I am not going to dwell on the take home message that it was positive and inhibited relapsing MS. This was an interesting trial design that recruitment was continued until set points were reached to ensure the trial delivered an answer.

“Ofatumumab was associated with lower annualized relapse rates than teriflunomide and showed benefit with respect to most secondary clinical and MRI end points but not confirmed disability improvement. Ofatumumab was associated with a higher frequency of injection-related systemic reactions, predominantly with the first injection, than was placebo injection. Larger and longer trials are required to determine the long-term effect and risks of ofatumumab as compared with other disease-modifying treatments, including other anti-CD20 monoclonal antibodies”

I sure that ProfG will have something to say when he gets back from his hols…..because whilst it ticked the boxes with regard to relapse rate, the disability was not that much different from teriflunomide.

The B cells were maintained at low levels…what happens to memory B cells, we can only guess. What happened to the anti-drug antibodies…fear not they’ll arrive

Ofatumumab versus Teriflunomide in Multiple Sclerosis.Hauser SL, Bar-Or A, Cohen JA, Comi G, Correale J, Coyle PK, Cross AH, de Seze J, Leppert D, Montalban X, Selmaj K, Wiendl H, Kerloeguen C, Willi R, Li B, Kakarieka A, Tomic D, Goodyear A, Pingili R, Häring DA, Ramanathan K, Merschhemke M, Kappos L; ASCLEPIOS I and ASCLEPIOS II Trial Groups.N Engl J Med. 2020 Aug 6;383(6):546-557. doi: 10.1056/NEJMoa1917246.

Background: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.

Methods: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.

Results: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, -0.15; 95% CI, -0.20 to -0.09; P<0.001). In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P = 0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P = 0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P = 0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end point. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group (placebo injections). Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups.

Conclusions: Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.gov numbers, NCT02792218 and NCT02792231.).

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21 comments

  • At least the approval of ofatumumab will answer conclusively if MS is a B cell mediated disease. And bring to a end the long running debate between Prof G and most of the barts team. However MD, its not looking good. With complete shutdown of inflammation by ofatumumab and only to beat aubagio disability progression by statistically meaningless amount means slow burn that is called the real ms by Prof g continues unabated. Isn’t it time to ditch b cell theory ? Changing ones view based on new data doesn’t mean you are wrong.

    • Why ditch B cell theory? It is clear that memory B cells are important in inflammatory lesion development and who knows, if used early on diagnosis as has happened with some pwms treated with alemtuzumab where there has been effectively disease cessation without disease progression, there is the possibility you could see the same with the more targeted anti-B cell DMTs, again if used early in disease. As it looks like neuroprotective agents are still a far off dream, the mantra of hit hard, hit early with what we have still holds.

      • what would you count as early in the disease? i keep seeing this term but am wondering what you would count as early

        • To me it would be on diagnosis, though I’m not a clinician and there is the obvious caveat that there may well have been clinically silent episodes before that.

        • The Alem clinical trial enrolled pwMS 2 years after diag in mean (compare to 6 years in mean for Ocr and Ofatumumab). I understand that Mousse Doc thinks that the BVL differences between them can be explain mostly by this time gap. So I guess just after diag or one or two years later can be consider ‘early’. In my view it’s also depends on your lesions burden and it’s need to be before any CDP occurs (EDSS 0 or very low and same for cognitive problem).

    • Happy to change my views, as to B cell theory this is another example that supports the B cell theory. It supports the view that it helps generate the lesions, if you have to deplete T cells to get effects on atrophy I have no problem, I would suggest CD8s are interesting. However, my current view it is is not T or B are the centre of the smouldering lesion. ….but yep please, please please start taking alemuzumab…..it will help recruitment for a study.

      You say you have complete shutdown of inflammation and it can’t beat teriflunomide and slow burn continues…fine its not surprsing because these agents do not touch this and the trials are too short to show much of affect in most cases but do the trial where you take these things straight from diagnosis (clinically isolated syndrone) and also seem to remember the teri atrophy data looking much better than I thought. I guess this trial is now been down and we will see what it shows.

      However I will say this, if you only go after the smouldering lesions and forget about the peripheral invading immune response you are making a very big mistake. You only have to look at the neurofilament data as a marker of nerve damage..the biggest inhibitor of neurofilament prodcution is block peripheral inflammation and I dont think there is any disagreement with the whole team on this

      • Thanks MD, MD2, very good points. Yes you are right to completely shutdown ms you need to shutdown damage from inflammatory lessons as well as the damage from smouldering ms. Isn’t the way forward using combination therapy to deal with different types of ms neurodegeneration?

        • That would be our big wish but progress on getting neurpprotectants into pwms as the second part of the strategy remains as frustratingly out of reach as it was since we started experimental work in this area a loooooonng time ago. If it finally happened we might really be getting somewhere.

          • “neuroprotectants”…Sorry..just don’t see how one invents a whole new class of drugs…if only it could appear out of the treatment pyramid like magic…ALS..ALZ..MS would all be sorted…..Biologic diseases need biologic treatments…”Better Living Through Chemistry”…was DuPont ad slogan from 1935-1982. Since 1999, their slogan has been “The miracles of science”…Neuroprotectant drugs would indeed be a miracle.
            https://en.wikipedia.org/wiki/Better_Living_Through_Chemistry

  • The NMSS website’s reporting of the trial includes:

    “Brain tissue loss was not reduced significantly more in the ofatumumab group.“

    So is it a case of getting more Ofatumumab into the patient or are the processes causing brain tissue loss (.smouldering MS) not affected by the mechanisms of the current DMTs ie other drugs are needed?

    I’ve heard comments on the blog that a DMT doesn’t get into the brain. Why don’t they do the reverse of a spinal tap ie inject the DMT through this route?

    • Hi Sid
      The blood;brain barrier has evolved to keep compounds in the blood including antibodies from getting into the brain. So whilst the barrier gets leaky around lesions, allowing entry of immunoglobulins (including ofatumumab), once the lesion resolves the barrier reseals, as shown by MRI. So this is why you’re never going to get much of a monoclonal antibody based drug into the CNS, unless directly injected into the CNS. This was tried with rituximab with not much success on disease, though peripherally, B cells were depleted (go figure). However, drugs such as cladribine do get across the BBB into the CNS and there is some evidence that oligoclonal bands can disappear as a result, which is potentially very important and needs to be followed up. Other drugs such as BTK inhibitors also can get into the CNS.

    • The flow from the spinal tap is down and out…this was shown with rituximab and it did not seem to deplete the B cells in the spinal fluid, this is the reason you have an intrathecal baclofen pump, it gets drug into the spine but the level in the brain is low and so you avoid the side effects. The alternative route is into the ventricles…shame is you have to drill a hole through the skull and inject through the brain. I think there are some people with mad idea to put rituximab into the ventricles to see if it depletes the plasam cells….Plasma cells dont have CD20 so it aint going to work.

      ProfG has suggested to give a higher dose of ocrelizumab e.g something like 1200mg to try and get more into the brain to help block the smouldering MS, the ofatumuab goes in a 20mg…not enough to get anywhere by the circulation, is this under dosing? As to trying to do something differnt in the brin NDG has been trying to do just that but COVID has put a stop to this

    • There are abundant papers on tertiary lymphoid tissue in the meninges in pwms. These follicular sites harbor B and T cells and unfortunately are not affected by peripheral immune therapies due to BBB restriction or poor absorption in the tissue itself.

      MD you are correct in that we are repeating ourselves, peripheral lymphocyte antibodies are effective in reducing relapse but are unable to penetrate the CNS to address smoldering MS. Sometimes I wonder if these well known researchers who are on these papers get tired of these pharma funded studies. “Running over the same old ground what have we found the same old….”

    • There are abundant papers on tertiary lymphoid tissue in the meninges in pwms. These follicular sites harbor B and T cells and unfortunately are not affected by peripheral immune therapies due to BBB restriction or poor absorption in the tissue itself.

      Yeah, we are repeating ourselves….peripheral lymphocyte antibodies are effective in reducing relapse but are unable to penetrate the CNS to address smoldering MS. Sometimes I wonder if these well known researchers who are on these papers get tired of these pharma funded studies. “Running over the same old ground what have we found the same old….”

  • Hi everyone and thank you MD for this post! Love this blog!

    I just read the full appendix of the article on nejm.org. It seems to me that the results of T2 lesions count are not as great as in the OPERA studies.

    In the OPERA studies, after rebaseline (https://www.ocrevus.com/content/dam/gene/ocrevus/hcp/images/charts-reductions-lesion-activity-two-desktop.png) the mean T2 number per year was around 0.06 (between year 2 and year 1 notably). In comparison, in the ASCLEPIOS studies, it seems to me (see pages 45 and 46 of the appendix) that the mean T2 number per year is near 0.72 (at year 2).

    Am I right? If so, how can we explain this (big, like ten times) difference?

    Thanks again.

    • It could be their expressing percentages differently. So if 1 is 100, then 0.06 is 6%. I’d bee very surprised if there was a great difference between ocrelizumab and this Ofatumumab. Latter is a copy cat even if its mode of action is not completely identical.

      • I agree with your conclusion but I don’t think there is a difference of percentages. Anyone of the Bart team to have an opinion on this ? Thanks in advance.

  • Seems like most of the MS websites are posting the results of this trial.
    https://multiplesclerosisnewstoday.com/news-posts/2020/08/06/novartis-announces-nejm-publication-of-phase-iii-asclepios-trials-demonstrating-superior-efficacy-of-ofatumumab-in-patients-with-relapsing-multiple-sclerosis/

    However, as always, the Barts team are the only ones discussing ALL of the results, not just those that help get the drug to market (e.g. Risk of developing anti-drug antibodies and superior performance of teriflunomide in the brain volume loss metric). Plus, it would appear the investigators in the study missed the opportunity to see how teriflunomide would have worked as an IRT after B cell depletion with ofatumumab, given that reconstitution is perceived to be faster (at least initially) with ofatumumab compared to other higher dose anti CD20 DMTs.

    Thanks MD for keeping us up-to-date and providing your honest assessment. I look forward to Prof. G’s thoughts on the results of the study. No doubt these are effective and beneficial drugs, yet as you recently indicated, high efficacy comes with higher risks.

    p.s. I am not surprised to see “person A, person B, and person C”, was involved in the study. Looks like their circle just keeps getting bigger. 🙂

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