Ocrelizumab: DODO vs. ADIOS, who will win?

O


Barts-MS rose-tinted-odometer: ★★

In response to a question over the weekend about what has happened to the DODO and ADIOS studies. Both are alive and kicking. The more insightful question would be ‘how can I support both the DODO (double-dose ocrelizumab study) and the ADIOS (adaptive dosing ocrelizumab study) studies?’.

Surely, the DODO and ADIOS studies are incompatible with each other scientifically? How can I, on the one hand, support a higher dose of ocrelizumab and on the other hand suggest reducing the dose in the longterm. The hypothesis is all about timing and how you use anti–CD20 therapies.

You need higher doses of anti-CD20 therapy initially as an induction strategy to purge the various B-cell compartments of memory B-cells, which house latent EBV and the highly autoreactive population of B-cells that drive and maintain the MS-state. This population of cells may reside in the deep tissues and/or the central nervous system, which is why we are also testing CNS penetrant anti-B-cell strategies, simultaneously. Time is short so we need to run trials in parallel.

However, once you have purged these compartments say after 2 years of treatment you don’t need to maintain such high-doses of anti-CD20 therapies that are then suppressing normal B-cell biology and immune responses, which result in longterm complications. This is why we want to use ocrelizumab as an immune reconstitution therapy, i.e. high-dose upfront followed by no treatment and wait to see if MS remains in remission or disease-activity returns requiring additional courses. The latter is one of the arms of our proposed ADIOS study. 

In reality, if we could convince a national funding agency, a pharma company or a wealthy philanthropist I would use anti-CD20 therapy as part of an induction-maintenance protocol. After two years of induction therapy with high-dose ocrelizumab, I would test different maintenance strategies in parallel. My agents of choice would be teriflunomide, leflunomide, IMU-838 (vidofludimus) or ASLAN003 (selective second-generation DHODH inhibitors), HAART (highly active antiretrovirals), famciclovir or another anti-EBV viral agent. The hypothesis is to allow B-cell reconstitution after anti-CD20 therapy in the presence of an anti-viral agent to prevent EBV reactivation and reinfection of new memory B cells. By doing this you will also be derisking the long-term immunosuppression associated with anti-CD20 therapies and prevent the development of hypogammaglobulinaemia. In addition, you will be allowing patients to respond to vaccines.

The problem with this trial proposal is the outcome measure; the power calculations are not trivial and the study would have to be very long. I also have reservations about whether or not the regulators will accept the induction maintenance strategy. Maybe we can sell it to them on safety, i.e. to prevent the development of hypogammaglobulinaemia and infections rather than on efficacy? If we go this route then there is only one agent we can use and that is teriflunomide, which is licensed to treat MS. As teriflunomide is coming off patent there is a chance the  NHS may be interesting in funding such a trial; i.e. it would save them money. This is something I am exploring as a proof-of-concept trial.  

The good news is that Roche-Genentech is testing the principles of the DODO study and announced at MSVirtual2020 two high-dose ocrelizumab trials (see below). These trials up the stakes in the anti-CD20 wars and I am confident that we need higher doses upfront to purge deep tissue and possibly CNS pools of B-cells. Please note that you don’t need higher doses of anti-CD20 therapy to suppress relapses and focal MRI activity you can do that with current or lower doses. I am confident both these studies will show that higher-dose ocrelizumab is superior to standard dose ocrelizumab on disability progression or smouldering MS, but not on focal inflammatory events. In relation to the latter, we have hit the ceiling already.

You need higher doses up-front to target the drivers of smouldering MS; i.e. disease progression independent of relapses, accelerated brain volume loss, slowly expanding lesions (SELs) and the subpial cortical lesions.  If these higher-dose studies are positive it will put clear daylight between ocrelizumab and the other anti-CD20 therapies and it would mean the ofatumumab and rituximab are currently being underdosed, at least initially in the first two years. But don’t we have a hint of this already? Ofatumumab was not better than teriflunomide at slowing down brain volume loss in year two of the ASCLEPIOS I and II clinical trials (NCT02792218 and NCT02792231) despite being superior to teriflunomide on relapses and MRI activity. The latter is more proof that focal inflammatory disease (relapses and MRI activity) is not MS but in response to what is causing the disease. The real MS is what causes smouldering pathology and end-organ damage.

DODO vs. ADIOS vs. iTeri: which one would I prioritise? Almost certainly iTeri; the iTeri trial makes the most sense in terms of our current understanding of the pathogenesis of MS, mode of action of anti-CD20 therapies and the long-term risks of chronic B-cell depletion.

Figure from the NEJM.

Hauser et al. Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med. 2020 Aug 6;383(6):546-557. 

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.).

CoI: multiple

Twitter: @gavinGiovannoni                                              Medium: @gavin_24211

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

27 comments

  • Thank you Prof G for posting ideas around these two studies again. I guess they are testing two different theories so not exactly a win and lose situation. Personally, I find the ADIOS is more important as it sheds light on an “exit plan” of CD20+ treatments, or at least make the treatment better tolerated for long-term treatment beyond 10 years.

    • Re: “Personally, I find the ADIOS is more important as it sheds light on an “exit plan” of CD20+ treatments, or at least make the treatment better tolerated for long-term treatment beyond 10 years.”

      The major motivation for this trial is the potential cost-savings to the NHS.

  • Thank you for this post ProfG. It makes me think of some questions I am curious about.
    How do we know if all B cells compartments have effectively been purged and if the DODO strategy did work at least on biological terms?
    If we get rid of all B cells do we get rid of EBV as well?
    If there are other autoreactive cells (e.g. memory T cells) could they be able to reinstate MS once all treatments are off?
    Is it possible that disability progression on Anti-CD20 is due to pre-existing damage i.e. the nerves already primed to die off?

    • We don’t have any method to test B cell compartments been purged, which is the purpose of the DODO study, expecting a better outcome than standard dose. And no we don’t get rid of EBVs as the epithelial cells are also infected.

      • We do but we have to look in the CSF and/or lymph nodes or using deep sequencing of what is available in the peripheral blood.

    • Re: “If we get rid of all B cells do we get rid of EBV as well?”

      Yes, there are a few case reports of HSCT and one case of an alemtuzumab-treated pwMS who become EBV negative. In other words, the treatment purged them of EBV.

      This is the rationale of cell-based therapies targeting EBV, be it MHC-matched CTLs or CAR-T-cells. However, we should be able to get there without a sledgehammer; potentially using an antiviral approach.

      • Thank you very much ProfG! I agree that we should come to the target following the softest possible approach even if I would go for sledgehammer if it is the only available approach 🙂
        I quickly searched and several anti viral drugs are not widely accessible either because of price or need of prescription. Do you think that a neuro would prescribe an off label antiviral based on the current evidences?
        There are some papers that address strategies to induce lytic cycle in EBV infected cells https://pubmed.ncbi.nlm.nih.gov/15827204/
        https://pubmed.ncbi.nlm.nih.gov/29632007/
        The latter looks interesting as zidovudine is one of the active principle of combivir used in one of the cases of disease remission with anti viral. Do you think these approaches could be of advantage with respect to the antiviral alone? Ous there an antiviral that could do the job and it is easily accessible?
        Thank you again for your continuous availability!

        • Re: “Do you think that a neuro would prescribe an off label antiviral based on the current evidence?”

          No. Neurologists’ shouldn’t until we have evidence that this treatment strategy works. This is what science is about, i.e. testing hypotheses.

  • “The problem with this trial proposal is the outcome measure”……I agree, even if you get the regulators to approve the iteri study based on safety, we still have the problem of measurable, reliable, and widely accepted bio markers and tests as a way to determine efficacy. As you said, suppression of relapses and facial MRI activity is not going to be sufficient.

    I used ocrelizumab as a first line therapy due to highly active disease activity at on-set. Ocrelizumab worked (stopped brain lesions and cervical spinal lesions) and I am glad I used it (and had accesses to it) first line. Became allergic to ocrelizumab after two years of treatment, so I switched to Teri. Plus, I felt like I was still progressing on ocrelizumab and would hit the “crap” gap between each infusion.

    Now, after about eight months on teri (low dose 7mg) I am still slowly progressing and experiencing some significant adverse side effects to teri (bone/hair loss). Good news is teri has kept MRIs clean and I am proof one can repopulate CD-19 b-cells in the presence of Teri. In addition, despite an initial b-cell spike (followed by a minor rebound flair up), my CD-19 b-cells did remain below base line levels (pre-ocrelizumab), which theoretically suggests a way to extend the benefit of an anti CD-20. Probably would not have had the rebound risk if I had started teri earlier than seven months post last ocrelizumab infusion. The problem is I still am slowly progressing and I have no medical way of telling why, so I am switching to cladribine in the hopes of a better CNS penetrant and outcome.

    I have been monitoring my lymphocytes (bloods) monthly since stopping ocrelizumab, low BMI, <40 yrs, and live in the U.S. So, if you ever need any real word data, you have my email 🙂

    • Re: “… problem of measurable, reliable, and widely accepted bio markers…”

      Most in the field would accept brain volume loss. In fact, the DELIVER-MS and TREAT-MS trials that are testing maintenance-escalation vs. flipping the pyramid are using brain volume loss as their primary outcome.

      • Interesting…..I participated in the TREAT-MS trial and the enrolling MS Center did not care or monitor my brain volume loss. Plus they ended the trial early due to COVID.

        I previously had a neuro say drinking a glass of water changes brain volume, so it is not a sensitive enough test🧐

  • Isn’t part of the problem the neurologists who “know” what MS is? MS is relapses and lesions you can see on an MRI.

    Once they’ve stopped new lesions forming and there are no relapses, as a busy neurologist they’ve done their job, the MS is “cured”. All the other stuff is just hypothetical nonsense and window dressing to try to justify funding for trials and treatment that’s unnecessary. “Sure patients whine about gradually getting worse and there is some brain volume loss. But look at the MRIs – there’s no lesions! And no relapses! Those are MS. MS is all but cured…”

    ProfG & crew, you have my sympathy in your efforts to try to persuade these “experts” that MS is not what they think it is. And you must succeed, our long-term health and well-being depends on it.

    The usual question: these treatment protocols would be for the newly diagnosed. They could mean that, “I’m very sorry but I’m afraid you have multiple sclerosis.” isn’t a life sentence.

    But what about for the veterans amongst us who’ve been chugging along all this time with inadequately treated disease? Could this protocol be adapted to try to protect whatever remains so that we too have the opportunity to try to halt neurodegeneration? And is there any news on protocols to even start to try to recover lost function?

    • Re: “Once they’ve stopped new lesions forming and there are no relapses, as a busy neurologist they’ve done their job, the MS is “cured”.”

      Yes, but we now know that many if not most of the patients who are NEAID (no evident inflammatory activity) come back with PIRA (worsening independent of relapse activity) or as I prefer to refer to it smouldering MS or the real MS.

    • Re: “..And you must succeed, our long-term health and well-being depends on it.”

      I am in the process of finishing off the second draft or a paper on smouldering MS that may trigger the shift we are trying to achieve.

    • Re: “But what about for the veterans amongst us who’ve been chugging along all this time with inadequately treated disease? Could this protocol be adapted to try to protect whatever remains so that we too have the opportunity to try to halt neurodegeneration? And is there any news on protocols to even start to try to recover lost function?”

      Yes, but this will need add-on combination therapies and a holistic approach to MS to tackle comorbidities, etc.

  • Can we please try HAART by itself before tossing it into some mix with anti-CD20 therapies? Or is this already in the works?

  • Very interesting post Prof, thank you. Where are things up to with ASLAN003? i remember reading that it was 30 times more potent than aubagio (Teri). I think you have a role in its development. Is this a product we should be getting excited about?

  • So, I was having lunch with my cousin and his friend yesterday. and the friend turned out to be an MD-PhD whose research area MRIs and slowly expanding lesions (and rim lesions (?)). He was surprised when I started asking about SELs and blood-brain barriers. He definitely thinks Ocrevus does cross the blood brain barrier in limited amounts and does help mitigate SELs (he has observed it in his studies!).

    He hadn’t heard about the DoDo and was excited to look it up when I mentioned it. He definitely thought this hypothesis was worthwhile to be studied. As an aside, he also mentioned Roche is testing using peritonal cavity for 15 minute ocrevus infusions. I was wondering if ProfG had any insights about it?

    • Not aware of the peritoneal cavity being used to deliver ocrelizumab, but that will be problematic in terms of staff and their training. An intraperitoneal infusion is not trivial and has potential complications associated with it, i.e. bowel perforation and peritonitis. There is a subcutaneous trial of ocrelizumab going on at present maybe that is what he was referring to?

      • I do not it was the subcutaneous trial. He did mention something used in dialysis and dialysis centers handling it, so I think it was the peritoneal cavity. Not a doctor, sorry if I am way off the mark here.

  • “Yes, but we now know that many if not most of the patients who are NEAID (no evident inflammatory activity) come back with PIRA (worsening independent of relapse activity)”

    In other words your DMT may cost $100,000 a year but it will not stop secondary progressive ms.

  • ADIOS rules! Yes I definitely agree with Prof G that anti- CD 20 should be administered after 2 years of high dosage ocrelizumab. This would surely significantly reduce cancer risks? And generally derisk long term immunosuppression.

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