Monday, 17 November 2014

ClinicSpeak: de-risking natalizumab

Imagine if we could clear MSers of JCV and eliminate the risk of PML altogether? #ClinicSpeak #MSBlog #MSResearch

"I was at a meeting last week and got into a debate with colleagues about treating MS. I made the point that only the highly-effective treatments are capable of switching off inflammation, allowing spontaneous recovery and preventing end-organ damage, when used early in the course of the disease. I asked knowing this who would not want to be on a highly-effective treatment? Their response was all about the risks of this strategy; downplaying the obvious benefits. However, if you could make natalizumab and alemtuzumab safe then yes, most neurologists would prescribe them first-line, assuming that they were affordable and available to all. I say this because pharmaceutical pricing is about the risk:benefit ratio and not the manufacturing costs. So if these drugs got safer, they may get more expensive; particularly in the US that runs a quasi-market. In comparison, in the UK once a drug price is set it is essentially fixed at the price until it comes off patent; this is not a market."

"Just imagine if the PML problem went away, and natalizumab was shown to be safe in pregnancy, who would choose anything but natalizumab to treat MS? Can we get rid of the PML problem? I think we can; it will take science, innovation and time. If we don't start now we will never find the solution."


"PML is caused by the JC virus, which is a member of the human polyomavirus family. JCV is a relatively simple virus, without a latency programme. JCV, therefore, persists in the body by remaining active; in other words it continues to infect cells, kill cells and then re-infect new cells. This means that the virus may be druggable; i.e. if Pharma can develop an anti-viral drug that interrupts the viral life cycle it may be possible to clear the virus from the body and hence the risk of PML will go away. We have a precedent for this, hepatitis C. The new anti-hepatitis C drugs target a critical enzyme, called the viral protease that the virus needs to maintain its cycles of replication. These new hepatitis C protease inhibitors block viral replication and as a result up to 98% of hepatitis C patients can now be cured of their infection. Can we do the same for the JC virus? I don’t see why not. I envisage a drug taken for a few months after which all JCV shedding will stop and because the virus is not active anymore and hence not stimulating the immune system the titre or level of antibodies to virus will drop. I call this a deboosting, in contrast to the boosting, antibody response."

"If you have been following this blog for some time you will be aware that a rising titre of antibodies to the JC virus is a risk factor for the development of PML. A rising antibody level indicates that be JC virus is active within the body and is stimulating the immune system to produce more antibodies. This is analogous to what happens when you have a booster vaccination to common infections, for example flu or tetanus."

"Do any of these observations have relevance for MSers on natalizumab therapy? Possibly. At the moment we assume that if you have anti-JCV antibodies you have the virus present in the body. This is not necessarily the case. Not all anti-JCV positive people shed the virus; therefore a subset of people with antibodies to the virus may have cleared the virus from the body and hence be at low risk of PML. This may explain why a persistently low titre of antibodies to JCV indicates a low risk of PML. This may simply indicate past infection and no active infection at present. In contrast those with a high level of antibody, or a rising level of antibodies, have ongoing active infection and a booster response and are much risk of developing PML. I now put much more weight on a rising antibody level than the absolute level."

"If you have a drug that interrupted the JCV infection cycle how would you test to see if it works? I would recruit a group of MSers who were found to shed JCV in the urine. I would then treat half with the drug and the other half with a placebo. The short-term aim would be to stop viral shedding in the urine and the intermediate to long-term aim would be to see a deboosting, or a lowering, of their antibody level compared to controls. This is not a new idea; I proposed doing this a few years ago with a selection of off-patent drugs that may work against JCV."


"Having an anti-viral that interrupted the JCV life-cycle would also be useful for treating PML, but it would also have wide use outside of natalizumab-treated MSers. I would envisage anybody who is JCV-positive needing to go onto immunosuppressive therapies having a course of treatment to clear them of the virus and hence lower their risk of PML in the future. For Pharma this makes the potential market for this product huge; hopefully this is a big incentive."

"There is a caveat to this strategy. JCV may live in parts of the body that can’t be reached by a standard antiviral drug, i.e. in a so called niche or sanctuary. It is possible the central nervous system (CNS) acts as a JCV sanctuary in those people destined to get PML. Why do I say this? For JCV to cause PML it has to acquire many genetic mutations and escape from the immune system. During this process the outer coat protein of the JCV mutates as it acquires the ability to infect glial cells, oligodendrocytes and astrocytes, cells that are only found in the CNS. This selection process is essentially evolution in progress and the virus acquiring these mutations needs a survival advantage. I can only envisage this happening close to the cells being selected for infection, i.e. the glial cells in the CNS. So if you already have virus in the CNS and you take an antiviral drug that does not cross the blood brain barrier you may not clear the virus. The CNS sanctuary, or niche, is a real phenomenon and is observed in HIV. Many HIV positive patients on ant-retroviral drugs have undetectable virus in their peripheral blood, but when you analyse their spinal fluid you still find virus. This happens because a large number of the current anti-retroviral drugs don’t cross into the CNS and hence the HIV virus can multiply unchecked in the brain. It has now been shown in HIV that the CNS compartment is an important place where HIV can acquire drug resistance; the low levels of anti-retrovirals, due to poor penetration, creates the environment that selects for drug resistance HIV strains. I find this fascinating."

"Getting rid of the PML problem will not derisk natalizumab completely. Why? There are other viruses that can infect the brain and spinal cord that need an appropriate immune response to be cleared. This is why even if you are JCV negative you are still at risk of other CNS viral infections and need to be vigilant. Take for example herpes encephalitis; I am aware of at least one death on natalizumab due herpes simplex virus encephalitis. In this case the presentation was very atypical and presented like a pseudotumour or large slowly expanding lesion. This is because the immune response to virus is kept at bay by natalizumab hence the herpes viral infection was more insidious in onset. We see this in patients with other immune deficiency syndromes. What about exotic infections? For example, dengue, Japanese B encephalitis or yellow fever. Again people on natalizumab are at risk of atypical exotic infections if they travel to place where these infections are endemic. Dengue is a potentially a big problem as you can’t be vaccinated against it. The bottom line is no drug will 100% safe in MS, but if we could sort out the PML problem and all MSers went onto natalizumab 1st-line we MSologists may just be out of a job. I say this in jest, but many a true word is said in jest."

"We have now launched a beta-version of our online App to inform you about your PML risk on natalizumab. We would appreciate it if you gave it a test run and provided some feedback."

CoI: multiple

12 comments:

  1. This is a brilliant idea. Prof G have you spoken to Biogen about this? Surely they would be interested in this proposal.

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    1. This is not brilliant, but pretty obvious. I am sure Biogen-Idec are on the case. What we need is more virologists working on PML and more chemists working on drug discovery.

      When I proposed the project to them several years ago the case for using the 3 specific drugs was weak. I think if I was in charge of the drug discovery programme at Biogen I would also have tossed it out.

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  2. Why only natalizumab? I thought you were such a fan of alemtuzumab.

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    1. We are talking PML risk, so the main problem at present is with Natalizumab as and if PML raises its ugly head with other MS drugs we hope aim to address that also.

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  3. Is there any news in the development of JC virus vaccine?

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    1. A vaccine won't cut it if you have pre-existing JCV as it hides behind the blood-brain barrier and antibodies cannot gain access.

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  4. How does JC virus respond to anti-virals in AIDS patients? It should be known, since PML is also seen in AIDS.

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  5. Dear Prof G, that sounds very interesting as a future approach, but what do you think about the biomarker L-selectin? That is already available today and it might help a lot in reducing the PML incidence (if it works) don't you think?

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  6. Hey, I have an idea:

    just make the JVC-Test less sensitive and less specific and all prbs are solved!

    \o/ YAY

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    1. I wonder how funny your comment would be to the families of the 109* people who've died from Tysabri-related PML so far or the 386* people who are living with the often devastating effects of PML ?

      * data from Sept 2014

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    2. Re: "I wonder how funny your comment would be to the families of the 109* people who've died from Tysabri-related PML."

      Well said, this is not a laughing matter. Every death from PML due to natalizumab is an avoidable death and attached to each death are spouses, children, extended families and friends. Each PML victim has their own narrative and we need to remember that.

      I have sleepless nights about patients of mine developing PML; we need to sort this problem out. If we do I may sleep better.

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  7. is anybody working on finding a solution to jcv. is it one of those things that wouldnt make enough money so they havent bothered. since it normally doesnt cause a problem. but when immunosurpressed it can be a major one. that was the first thing i thought of .. find a solution to jcv.

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