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Prevymis (Letermovir) for CMV - FDA approved!

Discussion in 'Antivirals, Antibiotics and Immune Modulators' started by OnlyInDreams, Feb 13, 2018.

  1. OnlyInDreams

    OnlyInDreams

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    I don't think folks in the PR community are aware of this because I'm not seeing any threads discussing it (which really surprises me). But this drug was FDA approved in November 2017 & made available for purchase December 2017. I just found out a few days ago. I just wanted to make everyone aware!!

    Keep in mind that this antiviral drug is only effective against CMV. It has absolutely no effect on any other viruses or bacterium. I've been on Valcyte for several years now. Everyone knows about the risks associated with taking Valcyte. So I'm ready to make the switch to a much safer and more potent alternative. Letermovir is non-toxic, where as Valcyte is very toxic.

    This drug is extremely expensive. To be exact, it costs about $434,000 for a 90 day supply. But with good health insurance, it is definitely affordable. For me, it would cost $120 for 90 day supply. But the tricky part is getting the insurance company to approve the prescription request. Currently I'm in the process of getting a specialist to make the request for this drug and then pray that my insurance company approves it. If anyone is lucky enough to get a Prevymis prescription, please let me know and please share status updates on your health, etc. while on the drug. When (if) I get my prescription I will do the same.

    Lets get this discussion started! This is a MAJOR breakthrough.

    If interested, here are a couple links to get you started on research & available data.

    https://www.centerwatch.com/drug-information/fda-approved-drugs/drug/100235/prevymis-letermovir-

    http://investors.merck.com/news/pre...ic-Stem-Cell-Transplant-Patients/default.aspx
     
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  2. Hip

    Hip Senior Member

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    You might want to edit the thread title (see "thread tools") and insert the fact that this is a cytomegalovirus antiviral, so that people can see this.


    The main advantage of letermovir over Valcyte seems to be that it is less toxic.

    But one disadvantage from the ME/CFS perspective is that letermovir does not readily cross the blood-brain barrier, at least in rats, 1 so may not be much good at targeting CNS cytomegalovirus infections. Whereas Valcyte readily crosses the BBB.
     
    Last edited: Feb 13, 2018
  3. Ema

    Ema Senior Member

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    I wonder how many of us have CMV without all the others though? I am not sure how much good it would do to rid myself of one, if there are three others waiting in the wings.

    Iā€™d still probably try it, except I doubt Medicare is going to pay any time soon.
     
  4. Hip

    Hip Senior Member

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    Are you sure that's the correct pricing? That would work out as $4800 per day.

    But here it says that the cost per day for Prevymis tablets is $195. That's still very expensive, but much less than $4800.
     
  5. OnlyInDreams

    OnlyInDreams

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    Sorry I miscalculated the cost. That was the cost for 1 package a day. Should have been for 1 package per month. Actual cost is about $14,300 for 90 day supply without insurance.
     
  6. OnlyInDreams

    OnlyInDreams

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    Great point. Perhaps the strategy would be to take both Valcyte & Letermovir for a while and then slowly taper off the valcyte.
     
  7. OnlyInDreams

    OnlyInDreams

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    Also Hip, I found this quote from the link you posted:

    "Organ distribution The distribution of letermovir may be influenced by the expression of OATPs as well as P-gp and BCRP as it is a substrate to these transporters. In albino rats, highest distribution was to the GI tract, bile ducts and liver. No penetration was observed to the CNS. However in another study in pregnant albino rats, the results indicated passage over the blood-brain barrier. The volume of distribution is dose-dependent likely due to the auto inhibition of OATP1B1/3 reducing distribution to organs expressing these transporters such as the liver."

    So in one study, there was no CNS penetration. But in another study, there was. So at least we still have the possibility of it crossing the BBB in humans.
     
  8. Hip

    Hip Senior Member

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    Well spotted. So letermovir might cross the BBB.


    In terms of the antiviral potency of letermovir in comparison to Valcyte, from what I can work out, letermovir is a bit more potent than Valcyte, but not hugely so. Perhaps around twice as potent, but it is hard to say with certainty.

    I have been working on a little pharmacokinetic project which calculates the antiviral power of various drugs as well as supplements and other compounds in vivo, which I am going to post on the forum at some point. In as far as my calculations are correct (and they may not be), here is the antiviral Potency Factor for Valcyte and letermovir that I calculated:

    Valcyte 900 mg daily for cytomegalovirus: Potent Factor = 4,500
    Letermovir 480 mg daily for cytomegalovirus: Potent Factor = 9,600


    So it shows that letermovir is around twice as potent as Valcyte, at the oral doses specified (increased doses will increase the potency).

    These pharmacokinetic calculation are based on taking the known antiviral potency figures for a drug in vitro, and then calculating what potency would be achieved in vivo when you take the drug orally.



    However, the problem with such comparisons is that the potency of an antiviral drug in cell line experiments depends on several factors, including the particular cell line used (some antivirals can work well with certain types of human cell, but perform more poorly with a different type of human cell), and also the particular strain of virus used (there are numerous strains of cytomegalovirus, and the same antiviral can be effective against one strain, but less effective against another).

    So for these reasons, it is not possible to reliably conclude that letermovir is twice as powerful as Valcyte, as the above figures indicate; but nevertheless these figures provide a ballpark sense of how letermovir compares to Valcyte, and both drugs seem to have similar potency.



    But potency is not the only factor that is important: it is also the antiviral mechanism. It is possible that the antiviral mechanism of letermovir might be better (or worse) than Valcyte at tackling the type of viral infection found in ME/CFS.

    Dr Lerner for example posits that the herpesvirus infections found in ME/CFS exist in the form of abortive infections, which he says antivirals like Valcyte and Valtrex cannot directly tackle (these two antivirals work against abortive infections in an indirect way, which is why according to Lerner it takes so long for these antivirals to take effect in ME/CFS patients).

    But if letermovir had a mechanism of action that could directly target these abortive infections assumed to exist in ME/CFS, then it could be the bee's knees in terms of an antiviral treatment for ME/CFS linked to cytomegalovirus.

    Looking at the letermovir mechanism of action here, it says that letermovir inhibits the activity of the DNA terminase complex to prevent production of mature viral genomes and the production of viable viral particles.

    So once cytomegalovirus has entered and infected a cell, letermovir prevents the virus from replicating its genome inside the cell, and also prevents it from making new viral particles.

    This is broadly similar to the mechanism of action of Valcyte, which works by preventing the virus from manufacturing viral DNA, so that the virus cannot replicate its genome.



    I don't know enough about abortive infections to say whether letermovir might be able to directly target such infections. And in any case, we don't know whether abortive infections really exist in ME/CFS (it's a viable theory that was proposed by Dr Lerner, but as yet there is little supportive evidence for the abortive infection theory ā€” though I do like this theory).
     
    Last edited: Feb 14, 2018
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  9. OnlyInDreams

    OnlyInDreams

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    Exactly. Letermovir disrupts the production and packaging of viral particles downstream from DNA synthesis. So DNA synthesis occurs, but without the output of infectious virions. So if Dr Lerner's theory is true, then theoretically this would eliminate (or at least reduce) the number of abortive infections (viral particles) at a much faster rate than Valcyte would. This would produce a far superior effect in terms of symptom relief and overall health.



    "Mechanism of action Selection and genotyping of a panel of mutant viruses that escaped letermovir inhibition indicated that the viral terminase complex, which plays a key role in cleavage and packaging of viral progeny DNA, is the target. The terminase complex minimally consists of a large and a small subunit that are encoded by two viral genes (UL56 and UL89). The terminase complex is thought to interact with premature viral capsids by binding to the viral portal protein pUL104. Recently, another viral protein (pUL51) has also been found in complex with pUL56 and pUL89, although its functional role within the viral terminase machinery remains to be elucidated. Consistent with letermovir resistance mutations that map to UL56, biochemical experiments and electron microscopy demonstrated that letermovir affects the formation of proper unit length genomes from viral DNA concatamers and interferes with virion maturation.

    Mechanism of Action: Letermovir Interferes with CMV Genome Cleavage and Encapsidation of Monomeric CMV Progeny DNA Mutant CMV isolates resistant to letermovir were generated in vitro. DNA sequencing identified mutations in the CMV UL56 terminase gene, and marker transfer analyses confirmed that these mutations were necessary and sufficient to confer letermovir resistance. No resistance-associated mutations were found in the UL51, UL89, or UL104 genes. While letermovir treatment leads to an immediate cessation of the production of infectious viral particles, it allows DNA synthesis to occur, thus providing DNA copies that are measured by the CMV DNA assay. Valganciclovir, in contrast, is a DNA polymerase inhibitor and thus has an immediate effect on the production of DNA copies.

    In the P001 study, CMV DNAemia has been used as a trigger for initiating pre-emptive therapy with GCV/VGCV. However, given that the postulated mechanism of action of letermovir is down-stream of DNA synthesis, CMV DNA might not be the optimal biomarker for the efficacy of letermovir prophylaxis. It may be that CMV DNA levels rise, but without the output of infectious virions that characterizes virologic failure. However, as there are no validated alternative biomarkers or PET initiation thresholds, the use of CMV DNA for monitoring and standard-of-care PET criteria is endorsed although this could be too conservative and result in unnecessary termination of letermovir prophylaxis."
     
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  10. OnlyInDreams

    OnlyInDreams

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    The key difference is that Letermovir prevents CMV replication as well as production of viral particles within the infected cell. So you wouldn't have abortive cells floating around. Where as with Valcyte, it only prevents replication (you still have the abortive cell, it just can't replicate itself).
     
  11. Hip

    Hip Senior Member

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    If letermovir were to effectively target abortive infections, then rather than the two years it typically requires to treat cytomegalovirus ME/CFS with Valcyte, you would probably get the same results in a matter of weeks with letermovir (assuming Dr Lerner's abortive infection theory of ME/CFS is correct).


    However, I can't judge from the antiviral mechanism given whether or not letermovir would work against abortive infections. Abortive infections are hardly studied at all, as they are generally thought to have little clinical significance, so we know very little about them.

    In an abortive infection, the virus enters the cell, but because certain types of cell do not contain the right "equipment" to allow the virus to complete its replication cycle (which would normally involve creating tens of thousands of copies of itself before these copies burst out of the cell), the virus is never able to reproduce.

    The virus keeps actively trying to replicate inside the cell, but never achieves this goal. It's like Groundhog Day for the virus. That is the nature of an abortive infection.

    I am not sure how one would go about trying inhibit an abortive infection, if one were designing an antiviral to do so.
     
  12. Ema

    Ema Senior Member

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    It looks like this drug is actually covered by my insurance, though the website has been a liar before.

    @Hip, do you think you would try it, if you had an easy source, if you were me? Non-medical advice, as always, :)

    I wonder why it doesn't work on EBV too, or if maybe it does, like some of the other antivirals are suspected of having activity against other herpes viruses? I haven't looked into the mechanism at all, obviously.
     
  13. Hip

    Hip Senior Member

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    I have only skimmed though a tiny bit of the material on letermovir, so don't know enough about it; but one thing I read was that it's less toxic than Valcyte, provided you don't go higher than the recommended dose. I'd have to look into it more, but that makes it attractive.
     
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  14. OnlyInDreams

    OnlyInDreams

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    From your link to the abortive infection thread, you wrote:

    "In abortive infections, although the virus cannot reproduce itself, it nevertheless makes some viral proteins inside the cell, and these may lead to cellular dysfunction.The virus may remain inside the cell as a chronic abortive infection."

    Given that info, consider this:

    "Letermovir interferes with maturation and packaging of viral particles but does not inhibit DNA synthesis. While letermovir treatment leads to an immediate cessation of the production of infectious viral particles, it allows DNA synthesis to occur, thus providing DNA copies that are measured by the CMVDNA assay."

    So to me, this means that Letermovir will prevent the virus from making viral proteins (particles) inside the cell. If that's the case, then there would no longer be any cellular dysfunction. Because virons produce viral proteins. So if you stop the production of virons/viral particles, then that would also stop the production of viral proteins. So eventually, all infected cells would be free of viral proteins. viral DNA would exist, but would have no impact on the body without the viral proteins.
     
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  15. Hip

    Hip Senior Member

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    I've just been reading the letermovir mechanism of action described here:
    So the way cytomegalovirus makes copies of its own genome is by creating a very long strand of DNA, with hundreds copies of the viral genome on the same strand, all back to back.

    It's then the job of the DNA terminase complex to cut this very long DNA stand into individual genomes.

    Letermovir interferes with this cutting process, and so stops the virus from creating any new single genomes that can be packed into new viral particles. The virus it still able to make hundreds of copies of its genome, all strung together in a long strand of DNA, but letermovir prevents the virus from cutting this stand into the individual genomes which are required to stuff into new viral particles. That's how it blocks viral replication.


    I don't think letermovir does anything to stop the production of viral proteins, as far as I can see.

    It may have some other effects that might inhibit abortive infections, though. I guess the only way to see if it works well for cytomegalovirus-associated ME/CFS is to try it. It will be interesting to see if any of the ME/CFS specialist doctors start using letermovir.
     
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  16. OnlyInDreams

    OnlyInDreams

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    The hundreds of copies of its genome is the viral DNA. We know that Letermovir does not stop DNA synthesis. But it does prevent the production of infectious viral particles. And if there's no production of infectious viral particles, then there's no disease.

    And viral proteins are the product of viral particles. So if there are no viral particles, then no viral proteins will be produced either. viral genome is the DNA, which is harmless by itself. This is my understanding of it.
     
  17. Hip

    Hip Senior Member

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    The genome is the sum total of all the genes (plus some noncoding DNA) that an organism possesses. So for example, a human being has around 20,000 genes, and all these genes strung together in one long length of DNA make our genome. Similarly for a virus.

    So although letermovir does not inhibit DNA synthesis like Valcyte does, which means that cytomegalovirus can still make its genes, and string these genes into its genome, and then string hundreds of genomes into a huge length of DNA, what letermovir does is prevent the virus from separating these genomes into smaller individual genomes.

    The virus in the cell may well be manufacturing proteins and using these proteins to build a viral capsid (the hollow container for the viral genome), but when it comes to filling the capsid with a newly-made genome, there are no genomes available, because of letermovir.


    Also, not all the proteins a virus makes are for building the capsid structure; viruses also manufacture non-structural proteins for other purposes, for example, to thwart the immune response, or to alter cellular functioning in a way that benefits the virus, or to help with capsid manufacture. These non-structural proteins can also cause problems for the cell.
     
  18. OnlyInDreams

    OnlyInDreams

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    But without the viral particles, why would the immune system need to respond? There's no threat because the virons aren't being produced and the existing ones will eventually die off.

    Would the problems that the non-structural proteins cause translate into CFS/ME symptoms? I doubt that they would. Not without viral particles.

    I am fixated on this. This is the bottom line when it comes to Letermovir:

    "Letermovir treatment leads to an immediate cessation of the production of infectious viral particles"

     
  19. Hip

    Hip Senior Member

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    You don't necessarily need to have virions or bacteria floating around in the blood or interstitial fluids of the body for the immune system to respond.

    The immune system will also respond to intracellular infections that exist entirely within cells. Such infections include the intracellular non-cytolytic enterovirus infections found in ME/CFS, and intracellular infections with bacteria such as Chlamydia pneumoniae (not all bacteria live outside of cells; many like Chlamydia pneumoniae live within cells as an intracellular infection).

    One way that the immune system can detect that a cell is infected with a pathogen is via the histocompatibility complex (MHC), a device that cells possess on their outer surface.

    It's the job of the MHC to present to the immune system the proteins that are being manufactured within the cell. When a virus or intracellular bacterium starts making its proteins inside a cell, the MHC will hold up fragments of these proteins for display outside of the cell to the immune system, and the immune system then knows the cell is infected, and will respond.

    So if you have an ongoing infection in the cells, such as the non-cytolytic enterovirus infections that are proven to exist in ME/CFS, or the abortive herpesvirus infections that are theorized (but not yet proven) to exist in ME/CFS, although neither infection produces any viral particles, they can still elicit an immune response. The cell signals to the external immune system that it is infected.

    And if for any reason the immune system is having trouble in clearing the intracellular infection (and this can happen for a number of reasons), then you have an ongoing intracellular infection which causes a constant immune response (possibly creating the symptoms of ME/CFS), but which the immune system cannot eradicate.



    Non-cytolytic enterovirus intracellular infections are an interesting area to study as a potential cause of ME/CFS, because we know these intracellular enteroviruses exist inside the cells of ME/CFS patients. There is a thread about them here.

    I wish someone would follow up on Dr Lerner's theories of abortive herpesvirus infections inside the cells of ME/CFS patients, as proving the existence of such infections I think would move ME/CFS viral research forward in a huge leap.



    But we don't know for sure that non-cytolytic enterovirus or abortive herpesvirus infections in the tissues of ME/CFS patients are the cause of the illness. Another possibility is that when an infection is able to enter the brain, then that causes ME/CFS. Three brain autopsies on ME/CFS patients all found enterovirus in the brain, whereas none of the control brains were infected.
     
    Last edited: Feb 15, 2018 at 10:07 AM
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  20. OnlyInDreams

    OnlyInDreams

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    Ok, so there would be an immune response. But with the cessation of the production of infectious viral particles, I would think the immune response would be less severe. So you would still have ME/CFS symptoms, just greatly reduced. Reduced further than what Valcyte is able to accomplish.

    And what about taking Valcyte & Letermovir simultaneously? That would be an interesting experiment for sure.

    I don't know if the brain infection is the cause or an effect of ME/CFS. But I do know that it is occurring. I personally experienced it on day 1 of my infection. My brain was on fire for like 3 days. I'll never forget that experience. But assuming Letermovir can cross the BBB (which was proven possible in at least 1 study), then the brain infection portion of the disease could be treated.

    I think the viruses are infecting anything and everything inside the body when the opportunity presents itself (brain, heart, lungs, blood cells, etc).
     
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