Trials going classical

T

One of the next new kids on the block is going to be Ofatumumab (Anti-CD20). There were positive data on the MRI scans and on relapse rate that puts it in the league of the big hitters. This is hardly surprsing as it is a Me-Too drug and does the same as rituximab and ocrelizumab. This data was shown at Ectrims2019 in the ASSCLEPIOS (Greek god of healing) trials. OPERA was the trial name for ocrelizumab (anti-CD20).

Assklepios The Geek God of Healing

So it seems we are going classical with the trial names as they are not an acronymn. But next year we will ge the phase III results of ublituximab (Anti-CD20) in the ULTIMATE trial…I wonder if this is the Greek god of Banking, as I am sure I can hear “Show me the money” as Pharma can scent the cash of following in the footsteps of others. We are now having a glut of Mods, we will soon have a glut of anti-CD20 antibodies.

Ofatumumab will be the first fully human antibody to hit the stands and is given monthly by subcutaneous injection. When asked what would Prof Hauser advise being the leader of the pack with ocrelizumab and now ofatumumab, he seemed to indicate it depends how forgetful you are:-). Do you fancy that hospital outing or stay at home for a self-injection?

However, whilst the data was impressive compared to teriflunomide, it is hardly surprising that ofatumumab beats teriflunomide. It was markedly effective at blocking relapses (ARR = 0.1) and MRI inhibited.

However, this is where Prof G pipes up what about the brain atrophy data and here it didn’t win. Prof Hauser says that’s because teriflunomide outperforms on brain atrophy but hey look at the neurofilament data there is highly significant benefit in neurofilament light loss with ofatutumumab.

Now you ask why select a competitor that you think you could lose against? That’s a question for the manufacturer.

You could also ask. Why not go head to head against the licensed anti-CD20? However, that would be commercial suicide if you lost.

Now I must say something. You can’t have it both ways. Teriflunomide was not that effective on neurofilament light loss…..so how can it be claimed it is so effective in brain atrophy change, if a common mechanim is at work here?

This I think occurs, because neurofilament is responding to inflammation induced nerve damage rather than the nerve loss driving the progressive atrophy. Therefore the brain atrophy and the neurofilament is measuring differnt things. Therefore neurofilament light is a surrogate of MRI activity and not progressive neurodegeneration that is not associated with active disease. We know that natalizumab is great at dropping neurofilament light levels too. This was also supported by that seen in the PROXIMUS trial of sodium channel blocker + disease odifying drug.

If you are a neurologist and want neurofilament levels tested contact NDG for details

I suspect that ProfG will have something to say on this and again the brain atrophy seen with ofatumumab is not in the ball park seen with alemtuzumab in its pivotal trial. Many neurologists will just see this headline result. Indeed maybe the extra depletion of T cells is the key. However, in this trial the median time from diadgnosis was about 8-9 years, which is about the same as cladribine, but 5-7 years later than the alemtuzumab trials. Is this the difference? I think this is possible. The brain atrophy data was about -0.6 in the CLARITY trails (8-9 years from diagnosis) compared to 0.2 in the ORACLE trial (0.5 year from diagnosis), which is about the rate of natrual aging and the same as seen with alemtuzumab (CARE-MS I. 2 years from diagnosis)

Maybe they need to do some studies in early MS and get to the bottom of this. Maybe if ProfG can do a DoDo ocrelizumab trial where you compare a high dose to a standard dose, it should be done ASAP after diagnosis and work it out if age and disease-duration is the difference. This could be well be the battle ground where you try and decide which treatment to use as they are very similar in their ability to inhibit relapse. Which anti-CD20 best inhibits brain atrophy. Will a low-dose injected into the skin, get into the brain verses a much higher dose given as an infusion. Is this where ocrelizumab takes on rituximab?

You can watch the session on the ECTRIMS2019 website

Much of what I learned about anti-CD20 was from talking to neurologists using the different formulations and dosing regimes. I didn’t know that some people were already using ofatumumab (human Ig) when rituximab (Chimeric mouse/human) had failed because of neutralizing antibodies. However, I know wonder if the cancer formulation has a limited lifespan when will it be canned to make way for the expensive MS drug. Would that be in the spirt of Assclepios or is that why he appears with a snake?

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3 comments

  • Thanks, great information.
    Alternatively, instead of a higher dosis of Ofatumumab, could you combine Ofatumumab with Teriflunomide?

    • Good idea, the concept of and induction therapy (depleter followed by maintainence of better tolerate agent) following a B cell depleter followed by something like teriflunomide had crossed-our mind. I don’t know where discussions are. Another idea may be also where does evobrutanib (BTK inhibitor) fit in. Based on the efficacy presented so far, it is a non-depleter and does not bat in the same range as the B cell depleters). The potential issue for teriflunomide is it blocks proliferating cells so it may effect repopulation of cells and contribute to lymphopenia. At ECTRIMS2019 there was a poster on teriflunomide and its ant-viral affect. ProfG has also suggested that teriflunomide may work better as a second line drug rather than a first line drug. We have found a paper that could support that view. I have been looking for papers to see it it hits memory B cells better when it is second line rather than first line. I have seen some data on second line use but do not know if there is a difference. In rheumatoid arthritis there is a difference and it hits memory B cells better as a second line rather than a first line treatmet. But that data is based on leflunomide (the precursor to teriflunomide) and the problem is the first line drugs in arthritis and not the same as in MS.

      So a hypothesis. However, we don’t used teriflunomide enough to get at the answer. We asked Genzyme and it seems they haven’t got the data or are keeping quite (so nothing new there :-() and we also asked a T cell lab that has the data. Within a short time we got a graph showing that teriflunomide is not that great at depleting memory B cells. However they didnt answer our question, even when asked a few times about the difference first and second line. Maybe we were on to something?

  • “.so how can it be claimed it is so effective in brain atrophy change, if a common mechanim is at work here?”

    You have to read more 🙂

    High-throughput screening for pharmacological compounds promoting p57kip2 nuclear shuttling in
    oligodendroglial precursor cells

    Drug repurposing is currently considered as a promising approach to overcome the inefficient regeneration
    capacity in demyelinating diseases of the central nervous system (CNS). In multiple sclerosis (MS) autoimmune
    attacks to oligodendrocytes and myelin sheaths lead to transient axonal impairment and eventually to axonal
    degeneration and permanent neurological deficits. In the adult CNS, a widespread population of resident
    oligodendroglial precursor cells (OPCs) retains the capacity to generate myelinating oligodendrocytes (OLs)
    throughout adulthood contributing to myelin repair. However, the myelinating capacity of those cells is limited
    and decreases during the disease course due to lack of stimulatory cues and the presence of inhibitory signals.
    We revealed that the subcellular localization of the p57kip2 protein (nuclear vs. cytoplasmic) is closely
    associated to the state of OPC differentiation in that nucleocytoplasmic shuttling constitutes a rate limiting step in
    cell maturation and myelination (Göttle et al., J. Neurosci. 2015). This research project is directed towards
    understanding of the underlying signaling pathways responsible for the nuclear export process, which might lead
    to the identification of new pharmacological compounds that could be used for the development of novel
    regenerative therapies for the diseased CNS. To this end, we have established and performed a high-throughput
    screening for pharmacologically active compounds to assess their impact on OPC differentiation (in vitro)
    reflected by p57kip2’s subcellular localization. Leflunomide, an analog of teriflunomide, which has been
    approved as a first-line treatment for RRMS in the USA and the EU, emerged as a first hit-compound from
    screening. Teriflunomide mainly acts via inhibition of de novo pyrimidine synthesis exerting a cytostatic effect on
    proliferating B and T cells. However, we could successfully show that it also exerts positive effects on OPC
    differentiation and myelination in vitro (Göttle, Manousi et al., J. Neuroinflam. 2018) proving the efficacy of our
    screening strategy. Apart from this compound, 22 additional substances were identified as promoting nuclear
    exclusion of the p57kip2 protein. We are currently following the same workflow to assess their potential in terms
    of oligodendroglial cell differentiation and myelination. Moreover, bioinformatics analysis is conducted in order to
    identify (common) protein targets which are most likely involved in the regulated shuttling process

    Glia 2019 ( That conference you were) 🙂

    Yes my country

    Guess M&M country too

    But she´s an emigrante now

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